Article ID: WMC002410 ISSN 2046-1690

Toll-like Receptors (TLRs) and Disease: Relevance to Pathology and Novel Therapy

Corresponding Author: Dr. Okom Ofodile, Research Scientist, Center for Cardiovascular Research (CCR ), Institute for Phamacology and Toxicology, AG : THEURING, , Hessische Strasse 3-4, 10115 Berlin, Germany, 10115 - Germany

Submitting Author: Dr. Okom Ofodile, Research Scientist, Center for Cardiovascular Research (CCR ), Institute for Phamacology and Toxicology, AG : THEURING, , Hessische Strasse 3-4, 10115 Berlin, Germany, 10115 - Germany

Article ID: WMC002410 Article Type: Review articles Submitted on:03-Nov-2011, 05:48:43 PM GMT Published on: 04-Nov-2011, 07:17:25 AM GMT Article URL: http://www.webmedcentral.com/article_view/2410 Subject Categories:IMMUNOLOGY Keywords:Innate Immune system, Pathogenic Microorganisms, Inflammation, Immunotherapy, TNF1-TLR Inhibitor How to cite the article:Ofodile O . Toll-like Receptors (TLRs) and Prion Disease: Relevance to Pathology and Novel Therapy . WebmedCentral IMMUNOLOGY 2011;2(11):WMC002410 Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Source(s) of Funding: This work is supportedsolely by Okom Ofodile and Children

Competing Interests: NONE

WebmedCentral > Review articles Page 1 of 26 WMC002410 Downloaded from http://www.webmedcentral.com on 08-Dec-2011, 05:17:29 AM

Toll-like Receptors (TLRs) and Prion Disease: Relevance to Pathology and Novel Therapy

Author(s): Ofodile O

Abstract endogenous stimuli, such as heat shock , necrotic cells, extracellular matrix breakdown products, and small synthetic molecules. Importantly, rapidly accumulating data have implicated the TLRs in the Transmissible spongiform encephalopathies (TSEs) or development and resolution of pathology in a wide prion diseases are a group of chronic, fatal range of neurological conditions. With regard to the neurodegenerative disorders of humans and animals, aforementioned observations, and coupled, with the which have the unique property of being infectious, margins of what we now understand about the biology sporadic or genetic in origin. Creutzfeldt-Jakob and activities of Toll-like receptors, it is conceivable to disease (CJD) in humans, (Sc) in sheep and suggest that these receptor proteins, the TLRs, may goats, and bovine spongiform encephalopathy (BSE) play important role to play in the pathology of prion in cattle are typical prion diseases. Classical CJD can disease. Hence, elucidation and understanding the be considered as sporadic, infectious or familial, cellular and molecular basis responsible for both the whereas the new variant of CJD (nvCJD) is biochemical and molecular alterations associated with considered a BSE derived human disease. The exact the interactions between the TLRs and pathogenic pathogenic mechanisms and the exact nature of the agent(s), and the key processes of the pathogenic infectious agent of this disorder remain uncertain, pathways in TSE pathology, and interactions between, however, it is largely believed that an abnormal form ( and the interdependence of, the innate and adaptive PrPSc) of a host cellular prion (PrPc) may immune responses may open a new dimension to compose the substantial parts of the infectious agent understanding prion diseases. and that various factors such as oxidative stress, inflammation, perturbation of glutamatergic Introduction homeostasis, over-reactivity of the localized innate immune system of the brain, and microbial attack are implicated in the pathogenesis of PrD. Until very Transmissible spongiform encephalopathies (TSEs) or recently the signal-transducing receptors that trigger prion diseases are fatal neurodegenerative diseases in the acute inflammatory cascade have been elusive. mammalian species that are sporadic, but also have However, this enigma has been recently elucidated been traced to mutations and to infectious with the discovery of a transmembrane receptor transmission, including iatrogenic transfer. TSEs protein family, designated, Toll-like receptors (TLRs). include , Creutzfeldt-Jakob disease (CJD), TLRs are a family of highly conserved, Gerstemann-Sträussler syndrome (GSS), and fatal germline-encoded transmembrane receptors that familial insomnia (FFI) in human beings, as well as recognize conserved products of a variety of scrapie in sheeps and goats, bovine spongiform pathogen-derived molecular patterns (PAMPs), such encephalopathy (BSE) in cattle, and encephalopathies as lipoteichoic acids(LTA), lipopolysaccharide (LPS), in mink, cats, mule, deer, elk, and several exotic peptodoglycan (PGN), flagellin, unmethylated DNA ungulates [1,2]. Neuron loss, spongiform degeneration with CpG motifs, viral double- stranded (ds) RNA and and glial proliferation are the main pathological other components of microbial cell walls. In the last consequences of TSEs [3, 4, 5]. Amyloid plaques are decade, advances in understanding mammalian host abundant in Kuru, Gerstermann-Sträussler-Schenker immune responses to microbial invasion suggest that and certain forms of sporadic CJD. Fluoride plaques, the first line of defense against microbes is the particularly common in new-variant CJD (nvCJD) are recognition of pathogen-associated molecular patterns composed of a central core of amyloid surrounded by (PAMPs) by the Toll-like receptors (TLRs). TLRs prominent microvasculation [6]. Abnormal PrPSc mediate the recognition of PAMPs and inflammatory accumulation occurs in the majority of, but not all, responses to a wide range of microbial products and prion diseases [7, 8]. The pathogenic mechanism they are crucial for effective host defense. Recent underlying these pathological conditions is largely discoveries revealed that TLRs also have important believed to be a conformational conversion of the role in recognizing and regulating responses to cellular prion proteinPrPc into disease-specific,

WebmedCentral > Review articles Page 2 of 26 WMC002410 Downloaded from http://www.webmedcentral.com on 08-Dec-2011, 05:17:29 AM

beta-sheet-rich forms (PrPSc or Prp-res) that possess suggesting that PrPc is essential for the development abnormal physiological properties such as detergent of prion disease serving as a template for insolubility and protease resistance, PrPSc or PrP-res conformational change [29].This notion is evidenced [9].Evidence indicates that PrPSc is substantially by Bueler and associates [30]. These authors involved in the pathogenesis of brain changes, and in demonstrated that PrPc knockout (PRNP-/-) mice are propagation of the transmissibility of the disease resistant to scrapie . The finding that PrPc is process, by converting PrPc into a likeness of itself [3, multiply glycosidated indicates that PrPc may be 9, 10]. The “protein only” hypothesis, which was later linked to signal tranduction pathway [31]. Because refined into “prion hypothesis” holds that TSEs are PrPc has been found to be localized in the synapse, distinct from infectious diseases caused by , some investigators suggested that the absence of , fungi , or viroids in that the origin of the PrPc may alter synapse formation suggesting an disease is related to conformational alterations of an involvement of PrPc in neurotransmitter system of ubiquitous protein, the prion protein, PrP, and that CNS [32, 33]. There is also increasing evidence that nucleic acids are not essential for the propagation of suggests functional roles for PrPs in the copper the infectious agent [9,11,12,]. Thus, according to metabolism [34, 35, 36]. Recent evidence indicates prion hypothesis: 1) the normal cellular form of that PrPc controls the survival of the challenged cells PrP(PrPc) is transformed into disease-related, and by governing the induction of pro-and anti-apoptotic possibly in itself infectious, scrapie form, 2) therefore signaling pathways [37]. PrPSc is solely responsible for the infectivity and Together, the above data suggest that disturbing transmissibility of prion diseases, for it it is the sole fundamental uncertainties remains in the pathology of component of the infectious particle, which is termed TSEs. For instance, microbial pathogen agent(s), prion, [12, 13] and the variations in the tertiary whose exact nature have yet to be fully resolved, structures of PrPSc would account for the existence of should be substantially involved in driving prion prion strains with distinct biological properties [14]. disease. Hence the etiology of prion disease is However, despite the above data, the” protein only” unknown. This presents a substantial obstacle to the hypothesis and the associated protein-only model development of effective diagnosis, therefore, to date; cannot explain all the existing data. The prion neither preventive strategies nor long-term effective hypothesis has not yet been experimentally proved [5, treatment modalities are available for these diseases. 15]. There are, at least, four hypotheses regarding the Nevertheless, abundant evidence now exists that identity of the infectious agent in prion disease: neuroinflammation, and oxidative stress-damage [16], virino [17], Bacterium [18] and prion [19]. Indeed, contributes to the pathogenesis of several it has been shown in vivo that PrPSc deposition in neurodegenerative disorders including Alzheimer’s neuronal tissue not expressing PrPc has no disease (AD) [ 38, 39] and prion diseases [ 40,41, 42, pathological consequence [20]. In addition, in both 43, 44, 45], and all these processes have been shown infectious and genetic models of TSEs typical to be engaged and mediated by Toll-like Receptor symptoms of disease outcome and neurodegeneration signaling actions. Therefore, at the margins of what we have been detected in the absence of observable now understand, a major event in elucidating a PrPSc [21, 22]. Additionally, in commensurate to this, plethora of fundamental uncertainties in TSE indeed, in vitro conversion experiments of PrPc to pathogenesis may largely rely on our increased PrPSc, in which protease-resistance was, achieved by understanding of both the nature of the exact a denaturation/renaturation procedure, resulting in infectious agent(s), and the nature of the receptors protease-resistant beta-sheet rich PrPSc but not intimately involved in mediating the inflammatory infectious PrPSc [23, 24]. Second, the “prion activities in the pathogenesis of prion diseases. hypothesis cannot explain the presence of many prion Until very recently, the signal-transducing receptors strains that retain and inherit unique incubation period that trigger the inflammatory cascade have remained [15, 25]. elusive. However, this uncertainty has been a few The cellular prion protein, PrPc, is a normal cellular years ago elucidated with the discovery of a glycophosphatidylinositol (GPI) -anchored transmembrane receptor protein family, designated, sialoglycoprotein encoded by the PRNP [26]. toll-like receptors. These advances in understanding PrPc is found predominantly in CNS, but a lower the molecular basis for mammalian host immune amount of it is also found in the other tissues [27, 28]. responses to microbial invasion suggest that the first Despite a wide range of postulations, the physiological line of defense against microbes is the recognition of functions of PrPc have not yet been fully understood. pathogen-associated molecular patterns (PAMPs) by Nevertheless, strong compelling evidence exist the TLRs (reviewed in [46, 47]. TLRs have been

WebmedCentral > Review articles Page 3 of 26 WMC002410 Downloaded from http://www.webmedcentral.com on 08-Dec-2011, 05:17:29 AM

identified as being part of a large family of also indicates that primary causes of such pathogen-recognition receptors that play crucial role degeneration could originate outside the central for the induction of both innate and adaptive immunity. nervous system. Most recent studies have implicated TLRs in Immunity to infectious agents is mediated by two recognition of proteinaceous molecules such as heat general systems, innate and acquired immunity shock proteins, and other endogenous ligands (reviewed in ref: [61, 62]. In contrast to adaptive including extracellular matrix breakdown products, immunity , the innate immunity appears early during chromatin-IgG, pulmonary surficants, necrotic cells [ evolution and has the ability to recognize pathogenic 48,49,50] and endogenous mRNA [51]. Heat shock microorganisms by germ-like encoded receptors, proteins have been implicated in a plethora of central equipped with defined specificities for highly events in prion disease pathogenesis [52, 53]. conserved structures present on most pathogenic Johannes van Noort and co-workers [54] have recently organisms [63]. The innate immunity, in contrary to demonstrated the presence and activities of TLRs in adaptive immunity, is activated immediately after the central nervous system, thereby indicating the infection and rapidly controls microorganism implication of these receptors in executing replication, until adaptive immunity takes over. physiological and pathophysiological processes in the The innate immune response is activated by a few CNS. Furthermore, Schluesener and colleagues [55] highly conserved structures present in most have reported that that astrocytes and microglia are pathogenic microorganisms, instead of by recognition activated upon intracranial injection of CpG ODN by a wide range of various antigens.These structures (synthetic oligodesoxynucleotides containing the are defined as pathogen-associated molecular unmethylated 5’-CpG-3’ dinucleotides motif). In patterns (PAMP) sensed by pattern-recognition addition to this, Hemmi and associates [56] disclosed receptors (PRP).Among the well-defined PAMPs are earlier that Toll-like receptor 9 (TLR9) was responsible bacterial lipopolysaccharide (LPS), peptidoglycan, for the transduction of inflammatory intracellular mannans, bacterial DNA and double-stranded RNA. signals upon stimulation with bacterial DNA and CpG PAMPs are believed to be produced almost solely by ODN. Supports for the aforementioned notion have bacterial pathogens and are are essential for the been evidenced by further studies [57, 59, 59]. survival or pathogenicity of microorganisms[64, 65, Together, these data indicate that TLR9 is expressed 66]Patter-recognition receptors are mainly expressed on astrocytes and microglia, and points to an on effector , such as dendritic cells (DCs), important role for TLR9-activated glial cells in macrophages and B cells. All PRRs are displayed by a CpGODN-induced neuropathological conditions. In given cell type and have identical specificities.When a this respect, I am tempted to suggest that TLRs may PAMP is recognized, all cells are immediately have an important role in the development and triggered to perform their effector functions, thereby resolution of TSE pathology because of their critical leading to a rapid innate immune response [67, 68]. role in initiation of inflammatory responses, and mediating a wide range of signal transduction Review pathways intimately associated in the development and resolution of pathology in a wide range of neuropathological conditions. Here I summarize the Toll-like Receptors current state of knowledge on TLR-associated Now, research over the last few years has greatly signaling, and interactions, alongside discuss the advanced our understanding of the mechanisms by broad implications of these interactions for the which the immune system functions, and especially, pathology of prion diseases, and concluding that the innate immune system [69, 70, 71]. In keeping with advances in understanding of the biology and TLR this, recent advances in understanding the molecular pathways may allow us to tackle a wide range of basis for mammalian host immune responses to challenges in immunology and medicine. microbial invasion suggest that the first line of defense against microbes is the recognition of TOLL-LIKE RECEPTORS (TLRs) pathogen-associated molecular patterns (PAMPs) by The finding that the CNS is not immunologically the Toll-like Receptors (TLRs). In addition, the findings privileged as was previously believed represents a of Lemaitre B and colleagues [72] and Poltorak A and major breakthrough and a milestone in the history of colleagues [73] led to the realization that the proximal immunological sciences [60]. This recent discovery of innate innate immune sensing tool of insects and the immune response in the brain revives the idea that mammals are related by descent, and thus further immunological challenges might well be etiological indicates a key pivotal role for TLRs in the primary factors in sporadic cases of neurodegeneration, and

WebmedCentral > Review articles Page 4 of 26 WMC002410 Downloaded from http://www.webmedcentral.com on 08-Dec-2011, 05:17:29 AM

recognition of infectious pathogens by mammals. The TLR signaling pathways mammalian Toll-like receptors, major integral TLRs activate distinct signaling cascades via four component of the innate immune system, are a family different Toll/IL-1 receptor (TIR) domain-containing of highly conserved, germline-encoded adapter proteins. The four adapter proteins are MyD88 transmembrane receptors that are critically involved in (myeloid differentiation factor 88), MAL/TIRAP mammalian host defense. It is now known that there (MyD88-adapter-like/TIR-associated protein), TRIF or are 13 mammalian TLRs, which can sense molecular TICAM-1/ Toll-receptor-associated activator of patterns that are common constituents of a wide interferon) and TRAM (Toll-receptor-associated variety of pathogens but are rarely found in the host; molecule). The aforementioned four adapter proteins 10 in humans and 12 in mice [74,75]. Structurally, transduce signals from all of the TIR domains, TLRs are characterized by the presence of a activating protein kinases and then the transcription leucine-rich repeats domain in their extracellular factors that lead to inflammatory effects. Recent regions and a Toll/IL-1R (TIR) domain in the discoveries disclosed the identification of a possibly intracellular regions. In respect of the amino acid fifth TIR adapter protein, designated, Sarm [83]. sequence and genomic structure, TLRs can be divided However, the function of Sarm is presently completely into five subfamilies: TLR2, TLR3, TLR4, TLR5, and unknown. TLR9. The TLR2 subfamily is composed of TLR1, Despite divergent PAMP ligands, all TLRs with the TLR2, TLR6, and TLR10, and TLR9 subfamily is exception of TLR3 activate MyD88-dependent composed of TLR7, TLR8, and TLR9. TLR1 and TLR6 pathways to induce a core of stereotyped responses form heterodimers with TLR2 [67]. such as inflammatory events. The pathways that TLRs serve to identify conserved products of microbial transduce TLR signals in mammals appear to have metabolism (PAMPs), such as lipoteichoic acids both similar and dissimilar characteristics from those in (LTA), lipopolysaccharide (LPS), peptidoglycan (PGN), Drosophila [84]. In Drosophila the Toll-IMD-pathways other components of microbial cell walls [76, 77, 67], are crucial for antifungal and anti-Gram negative which enables the innate immune system to recognize bacterial responses, respectively. In mammals the invading microorganisms and to induce a protective host defense against microorganisms mainly relies on immune response. pathways that originate from the common TIR domain Recent discoveries disclosed that TLRs do not only of TLRs. The TLR family signaling pathway is highly mediate recognition and inflammatory responses to a homologous to that of IL-1R family. Both TLR and wide range of microbial products but also to IL-1R interact with an adapter protein MyD88, which non-microbial endogenous proteinaceous molecules, has a TIR domain in its C-terminal segment but a heparan sulfate and RNA, DNA and small molecular death domain (DD) in its N-terminal segment instead synthetic products [50, 78,79,80, 51]. The TLRs, of the transmembrane domain found in TLRs. MyD88 hence, play a key central role in innate immunity by associates with both the TLRs and IL-1R via recognizing conserved molecular patterns and interaction between the respective TIR domains. Upon generating signals leading to the initiation of an stimulation by a ligand, MyD88 recruits a death adaptive immune response, thereby serving as an domain-containing serine kinase, the IL-1R important link between the innate- and the adaptive –associated kinase (IRAK (IRAK 1 and IRAK4). IRAK arms of the immune system. Recent discoveries is activated by phosphorylation through its N-terminal disclosed the identification of a human TLR11. This death domain and then activates TNFR associated was originally isolated from murine. Murine TLR 11 factor 6 (TRAF6) to stimulate IKappaB Kinase (IKK) appears to be closely related to TLR5 and it is complex and MAP kinase. Phosphorylation of IkappaB expressed abundantly in kidney and bladder. by IKK complex induces the degradation of Ikappa B TLR11-deficient mice are reported to be highly through the ubiquitin-proteasome pathway, and susceptible to infection of the kidney by uropathogenic subsequent nuclear translocation of liberated bacteria [81], suggesting that TLR11 play important NF-kappaB mediates transcription of pro-inflammatory role in urinary tract infection. The function of the cytokine gerne [85, 86]. human TLR11 is not known because of the presence The TLR3 ligand, double-stranded RNA has been of a stop codon in the gene [81]. Important updates reported to induce the activation of NF-kappaB in suggested that a microbial profilin-like molecule MyD88 knockout (KO) mice, thereby buttressing the isolated from the protozoan parasite Toxoplasma notion that TLR3 signaling is independent of MyD88 gondii (T. gondii) functions as a ligand for TLR11 [ 82]. [87] Furthermore, signaling can occur independently of This profilin-like molecule (a protein) was shown to MyD88 for TLR4, which also activates NF-kappaB trigger IL-12 through TLR11. through the adapter protein TIRAP and for TLR3, as

WebmedCentral > Review articles Page 5 of 26 WMC002410 Downloaded from http://www.webmedcentral.com on 08-Dec-2011, 05:17:29 AM

indicated above, which induces an antiviral interferon uncertainties remain; the true nature of the causative (IFN)-? response through TICAM-1[67; 88]. Recently, agent (unconventional virus, virino, bacterium, fungus a germline-induced mutation in TRIF led to or “prion”?), mechanisms underlying the conversion of identification of another adapter molecule with a TIR PrPc to PrPSc, the preference of PrPSc accumulation domain; TRIF-related adopter molecule (TRAM), in glia and neurons or both, accurate pathogenic shown to be required by TLR4, but not TLR3-mediated mechanisms of neurodegeneration, precise modes of IFN response. In Tram-deficient mice, LPS induced infection, transmission, definite physiological functions persistent NF-kappaB activation, whereas the of PrPc and exhaustive structural characterization of expression of IFN-inducible was defective, PrPc and its pathogenic isoform, PrPSc [98, 99] thereby strongly pointing to a crucially pivotal role for Hence, a plethora of fundamental uncertainties still TRAM in the Toll-like receptor 4-mediated remains in prion disease biology and pathology, as MyD88-independent signaling pathway[ 89, 90] .These previous described. Among all these, the most compellingly indicate that studies designed to pressing and conflicting question is that of the true determine the activities of TLRs in any specific nature of the causative agent in prion diseases. pathological condition, whereby strictly Support for this notion is evidenced by the following MyD88-deficient model was tested (solely putting data: MyD88-dependent pathway into consideration), could Earlier biophysical studies carried out by Eigen M. almost impossibly lead to findings, which could be [100] conclude that the infectious unit in vivo does not enough to categorically rule out the involvement of considerably correspond with an in vitro form of TLRs in the development and resolution of the aggregated prion proteins, thus strongly indicative of pathology in the concerned model, strongly suggesting the involvement of a non-prion protein identical that the earlier reports by Prinz et al [ 91 ] that Toll-like pathogenic agent in the orchestrated network of receptors were not involved in the pathology of TSE events intimately associated with the pathogenesis of disease should not be considered as very accurate. prion diseases Thus, individual TLR signaling pathways are divergent, Bacterial Involvement although MyD88 is common to almost all TLRs. In spirited and thorough studies, coupled with Nevertheless, it has become increasingly clear that enormous patience and determination, Bastian F.O. there are MyD88-dependent and MyD88-independent and associates [101, 102, 103, 104, 18, 105] followed pathways. Further support for this notion is evidenced up progressively the involvement of a bacterium, by a huge body of important updates [92, 93, 94, 95,]. named, Spiroplasma, which belongs to a large family Judging from the enormous interest in research on of mycobacterium, in the pathogenesis of these transmembrane receptor proteins, the TLRs, it is Creutzfeldt-Jakob disease. Support for this notion has very likely that more Toll-like receptor ligands and also been evidenced by studies carried out by others signaling pathways will be identified in the future. It is [106, 107, 108]. Spiroplasmas are helical also of note that signaling pathways mediated by mycoplasmas that play a significant role in insects and Toll-like Receptors have also been revealed to be cell plants diseases [109] and they are also found in type-specific [96, 97].This indicate that , under certain arthropods that are likely to bit animals and humans, conditions, some cells and tissues might be prone to such as such as ticks and mosquitoes [110]. This favor this pathway to the other. The molecular subject (Spiroplasmas and their characteristics) has mechanisms underlying this have yet to be fully been recently reviewed by Gasparich G. and resolved. associates [111, 112] and comprehensive and detailed EVIDENCE ARGUING IN FAVOR OF MICROBIAL disclosure of the morphological and the ultrastructural INVOLVEMENT IN DRIVING PRION DISEASE aspects of spiroplasmas have been earlier The realization that a ubiquitous protein called, prion demonstrated by Cole and associates (109). The protein, plays an important role in the pathology of earlier report of Bastian FO [101] demonstrating the transmissible encephalopathies is a milestone, and inclusion of Spiroplasma-like molecules in CJD, was represents one of the most gratifying aspects of followed by a plethora of data from both Bastian and research carried out on transmissible associates,and other various laboratories encephalopathies during the last five decades. This substantiating and strengthening the notion, that discovery, concomitantly led to the birth of the “protein Spiroplasma-associated inclusions have a role in only” hypothesis [11], which was later refined into TSEs pathogenesis [101, 102, 103, 18, 104, 105, 106, prion hypothesis [12, 9]. Albeit, recent intensive 107, 108] The most recent work of Bastian and researches and significant advances in the province of associate on this subject, overwhelmingly and most prion diseases in the last ten years, fundamental compellingly implicated Spiroplasma sp (a

WebmedCentral > Review articles Page 6 of 26 WMC002410 Downloaded from http://www.webmedcentral.com on 08-Dec-2011, 05:17:29 AM

Mycobacterium) in the pathology of TSEs [18]. be implicated in driving prion disease, 2) that the TLRs Sequencing of the amplified PCR products of may have critically important role in mediating the Spiroplasma 16S rDNA robustly confirmed the pathology of prion disease, and finally 3) the TLRs, presence of Spiroplasma –like DNA (Spiroplasma 16S indeed, represent attractive target for pharmacological rDNA) in all the tested (5 in number) of TSE brains. interventions in the development of novel approaches This result presents a very clear and reproducible for the management of TSE diseases and a variety of evidence for the involvement of a bacterium in TSE other pathological conditions. pathology. Consistent with this notion, Ebringer and C-reactive Protein co-workers earlier suggested the involvement of C-reactive protein (CRP) is a serum protein that is another bacterium, Acinrtobacter calcoaceiticus, in the massively induced as a part of innate immune brain of a BSE-affacted animal ([113]. Additionally, in response to infection or tissue injury. The ability of commensurate to this, several lines of data have CRP to recognize pathogens and to mediate their demonstrated the ability of various anti-bacterial drugs elimination by recruiting the complement system and ( antibiotics) to suppress the progression of TSEs and phogocytic cells makes CRP and important in some cases , also to significantly hinder the component of the innate arm of the immune system, conversion of PrPc (PrPsen) into PrPSc (PrPres) [ 114, whict is solely responsible for the first line of host 115]. Now, as we have been thought, the cell wall is defense. According to the prion hypothesis, the main responsible for many of the characteristic properties of proteinaceous component in TSEs is the prion protein, bacteria (e.g. acid fastness, slow growth, resistance to PrPc, whose misfolded isoform, PrPSc, is suggested detergents, resistance to common antibacterial to be solely responsible for the infectivity and antibiotics, antigenicity). In agreement with this, the transmissibility of TSE diseases. Aside from prion mycoplasma, a bacterial family to whom Spiroplasma protein, however, a large number of other proteins sp belongs, do not have cell wall, and as a result, the have been localized to the TSE-affected brain. These mycoplasma are resistance to penicillins, include, for instance, serum amyloid component (SAP) cephalosporins, vancomycin, and other antibiotics that in mice Coe J. and associates [120] and C-reactive predominantly interfere with the synthesis of the cell protein (CRP) and IL-6 in CJD (121). Equally, in other wall [116]. Theses findings are consistent with earlier related neurodegenerative disease such as AD, acute report showing that spiroplasmas were highly sensitive phase reactants including CRP have been located in to antibiotics such as tetracycline, and other antibiotics the diseased brain tissues [122, 123, 124, 125, 126]. [117]. Furthermore, neither penicillins, nor very closely Mouse serum amyloid component (SAP), a major related antibacterial antibiotics, as previous described, acute phase protein, is a physiologic and functional have been reported to confer proctection to TSE counterpart of C-reactive protein (CRP) in humans. [116,117]. Hence, essentially, the above data strongly These proteins belong to the member of pentraxin suggest involvement of microbial pathogenic agent(s) family of proteins and they are potent acute phase in the pathology of TSEs [101, 102, 103, 18, 104, 105, reactants, characterized by by the cyclic pentameric 106, 107, and 108]. In addition to this, Seya and structure; these proteins interact with their ligands in a Matsumoto [118] have recently disclosed that the calcium-dependent manner [127, 128, 129]. They are functions of three forms of a mycoplasma mainly serum constituents and are not formed in the lipopedtide/protein, designated, brain under normal circumstances. On the other hand, macrophage-activating lipopeptide 2(MALP-2), P48, under pathological conditions, associated with and M161Ag, which were isolated from a mycoplasma, microbial attack, the concentrations of C-reactive M fermentans ( which thus belongs to the same family protein, for instance, rises dramatically in host defense as its close relative, Spiroplasma sp), were largely against the microbial attack. CRP has mediated by Toll-like receptor 2. These protein Ca2+-dependent binding specificity for molecules exert similar immunomodulatory effects on phosphocholine (PCh), a constiruent of many bacterial macrophages and dentritic cells. Immunomodulatory and fungal polysaccharides and most biological cell effects such as cytokine induction, NO production and membranes [130, 131]. Consistent with the primary maturation of antigen-presenting cells. M161Ag has function of CRP, CRP was discovered and named also been associated with the capability to induce in because of its reactivity with the PCh residues of vitro apoptotic cell death and to induce complement C-polysaccharide (PNC) , the teichoic acid of activation by binding macrophages via complement Streptococcus pneumonia [132], pointing to an elements C3b/C3bi and their receptors [119]. Together, important role of TLR in mediating the actions of CRP. essentially, the above experimental evidence strongly This notion is recently evidenced by Greenhalgh and suggests that; 1) microbial pathogen agent(s) should co-workers [133]. These investigators provided

WebmedCentral > Review articles Page 7 of 26 WMC002410 Downloaded from http://www.webmedcentral.com on 08-Dec-2011, 05:17:29 AM

evidence indicating the two components of the LPS result of microbial attack largely of bacterial and fungal receptor complex, CD14 and TLR4 should participate origins and this represents the fundamental function of in the cellular and molecular events controlling the CRP, 2) the expression of pentraxin in TSE strongly induction of acute phase proteins, SAA and SAP, in indicates the involvement of systematic inflammatory the lever after burn injury.. CRP is also bind other events in the pathophysiology and /or pathogenesis of constituents, which do not contain phosphocholine TSEs, 3) the generally believed “Marker” function of (PCh), such as small ribonucleaoprotein particuiles CRP is , indeed, purely a secondary function, which is [134]. Ligand-complexed CRP is recognized by C1q of mere diagnostic importance, 4) the reported and efficiently activates the classical pathway of expression- and up-regulation of CRP in TSEs [121], human complement system [135, 136]. It has also could , therefore, very conceivably, be indicative of the been proposed that CRP working in concert with the presence of exogenous microbial agents, largely , if complement component plays a role in the clearance not, solely , of bacterial and fungal origins, consistent of apoptotic and necrotic cells, thereby contributing to with the reports previously described [143, 145, 147, restoration of normal structure and function of injured 146]. Finally, the upregulation of CRP in the context of tissues [137]. However, as with most other elements of fulfilling host defense function againt pathogenic immunity, CRP has the lineage, the appropriate microorganisms has been reported to be also receptors, and the capacity to participate in both implicated in Aspergillus fumigatus conidia-induced potentially destructive inflammatory responses and attack [148] and in malaria-parasite-related attack , as potentially protective responses. Thus recent well [149]. The above observations, indeed, do not discoveries have implicated C-reactive in reconcile with the “prion hypothesis”. Taken together atherogenesis [138, 139], mediation of tissue damage with the evidence that Toll-like receptors mediate the in acute myocardial infarction [140] and in the process biological effects of CRP [133,150], coupled with the of “autotoxicity” in neurodegenerative disorders [141, margins of our present understandings of the biology 142]. Despite the above mentioned observations, and actions of TLRs, the above observations strongly however, the functions of CRP are yet fully to be strengthens the notion that Toll-like receptors should elucidated: Nevertheless, it is now well established have important role in the pathphysiology and that CRP, in host defense against pathogenic agents, pathogenesis of prion disease, exerts three major functions: activation the TOLL-LIKE RECEPTORS SHOULD HAVE A ROLE complement system; opsonization and the induction of IN THE DEVELOPMENT AND RESOLUTION OF phagocytosis [143]. Therefore, a very important PRION DISEASE PATHOLOGY function of CRP that could hardly be overlooked is its Cross-Talk with Bacterial CpG-DNA and TLR9 links ability to offer protection against microbial agents. This Innate and Adaptive Immunity is believed to be the primary function of CRP, whose It has been well established for decades that bacterial blood levels increases from almost zero to several DNA is immunogenic in vertebrates. Introduction of hundred micrograms per milliliter during inflammatory bacterial DNA in mice induces anti-DNA antibody and events in a variety of pathological conditions [144, NK cell activation. . In 1995, Krieg et al. [151] using a 145]. In addition to this, recently, Szalai AJ [143] lent B cell proliferation essay discovered that further support to this notion and extended on it by 5´-CpG-3´dinuclöeotides with selective flanking bases reporting that the CRP primarily functions in host are important for the immunogenicity of bacterial DNA, defense against microbial pathogen agents of largely thereby disclosing the sequence –specific bacterial, in the first instance, and fungal origins. This immunogenic characteristics of bacterial DNA. In notion was consistent with earlier studies carried out addirtion to this, in 1998, Jakob and associates [152] by Du Clos and associate [146, 147]. .Xia et al. demonstrated that bacterial DNA induces strong Th reported the ability of CRP to offer protection against 1-like inflammatory responses .The usage of this heightened inflammatory response mediated by sequence is suppressed in mammals and that such as lipopolysaccharide, which are released by the eukaryotic CpG motifs are preferentially methylated, infectious agents [147]. This finding may be which then abolishes their immunogenic potential. considered consistent with the reports of Coe and Following the work of [153], in 2001, Hemmi et al. [56] colleagues [120], Peyrin and colleagues [40] and disclosed that a member of the Toll-like receptor family, Sharief and associates [42]. These investigators TLR9, is the true receptor for the CpG motif-containing demonstrated, totally, independent from one another oligodeoxynucleotide (CpG-ODN). Accordingly, the that systemic inflammatory responses have pivotal ability of the TLR9 to satimulate the vertebrate innate role in the pathophysiology/pathogenesis of TSEs. immune system , and subsequently that of the Conclusively, 1) CRP is usually over-expressed as a adaptive immune system, presents TLR9 agonists as

WebmedCentral > Review articles Page 8 of 26 WMC002410 Downloaded from http://www.webmedcentral.com on 08-Dec-2011, 05:17:29 AM

attractivetarget for the development of highly effective products, and dsRNA, and also by endogenous mRNA, vaccines for infectious diseases, and as well as a as previously described. Support for this notion is stand-alone therapies or in combination with other evidenced by recent studies carried out by Bacot and therapies in other diseases such as cancer. Advances associates [162], for instance. These investigators in this field of research have led to the discovery of demonstrated, in a set of series of thorough and different types of CpG -ODNs, and disclosed that the elegant experiments, the activation of NF-?B signaling biological activity of CpG - ODNs is not restricted to pathway in monocyte-derived DCs, which led to the stimulatory cells of the primary. Recent advances production of inflammatory cytokines and further revealed that CpG- ODNs also activate cells in the differentiation of DCs by PrP106-126. These finding cental nervous system. For instance, particularly indicates that PrP106-126 (a peptide mimetic of the microglia and astrocytes present in the brain were pathogenic PrPSc) has the ability to mature and induced to upregulate their expression of cytokine and activate DCs as determined by the increased chemokines following exposure to CpG -ODNs [57]. expression of MHC classII (HLA-DR), costimulatory These observations strongly suggest that CpG- ODNs molecules CD40 and CD80, and the maturation can directly activate immunologically relevant cells in marker, CD 83. This study also lends support to the the central nervous system. Now, in the relentless notion that a proteinaceous molecule, in this case, efforts to eventually work out effective therapeutic pathogenic prion protein, PrPSc, (its mimetic) is in a approaches for TSE disease management, Hans full position to mature and activate DCs. However, Kretzschmar and co-workers [154] recently revealed despite the elegancy and the convincing strength of that appropriate employment of CpG the study, essential questions were left open. These deoxyoligonucleotides may have a role in significantly include the following points: 1) did PrP106-126 bind delaying the progression of TSE disease and may, at directly to the DCs or was the binding activity, as it least, be beneficial as a potent post-exposure should be expected, mediated by appropriate cell prophylactic measure. Thus, essentially, the above surface receptors(s). In this context, it is reasonable to data widely imply that pathogenic agent of bacterial assume that the activities of PrP106-126 could be best origin consistent with the compelling findings of carried out with the help of appropriate cell surface Bastian et al [101, 102, 103, 18, 104, 105, 106, 107, receptors, which could then effectively mediate, and 108] may have a role in driving the prion disease, and possibly regulate the activities of the PrP106-126 that endosomal –lysosomal compartmen, earlier peptide fragments. In the face of this problem, and disclosed as the major location for PrPSc synthesis based on our present understanding, it is reasonable [155], may represent a potential compartmental target to contemplate that coordinated association of for TLR-associated therapeutic interventions. PrP106-126 with surface receptor proteins should be Furthermore, the above data are consistent with the required to enable a successful interaction between concept of protective role of innate immune system. the PrP106-120 and the DCs. Now, at the margins of Therfore, on the basis of the aforementioned what we now understand about the biology and the observations , it is tempting to suggest that innate actions of TLRs, albeit that, there are also other immune system is an important player in TSE available surface receptor proteins [48], it is pathology, and that TLRs may have important role in reasonable to contemplate these family of driving the pathology of TSE disease. Hence, transmembrane receptors may participate directly or increased understanding of the activities, and biology indirectly in this event. As earlier reported by Lee et al. of TLRs may bear relevance to pathology and [163, 164], a G protein-coupled receptor formyl management of TSE diseases, and other peptide receptor-like 1 (FPRL1) has been suggested neurodegenerative diseases . to mediate the binding activities of PrP106-126, but PrP106-126 (a peptide mimetic of PrPSc) can with low interacting affinity to PrP106-126. This mature and activate Dendritic Cells (DCs) strongly indicates that other receptor proteins should The activation of monocyte-derived cells is largely be required in the mediation of PrP106-126 believed to play a pivotal role in the inflammatory binding-activities, to enable the protein PrP106-126 process leading to the pathogenesis of many achieve its objective effectively. Furthermore, Lee et al neurodegenerative diseases such as Alzheimer’s [163, 164] also concluded that FPRL1 also mediate disease and prion diseases [156, 157, 158, 159, 160]. the activities of amyloid beta peptide (Abeta 42) and Denditic cells have been shown to mature and that of almost all amyloidogenic molecules. Now, become highly activated in response to several George Perry and associates [165] recently disclosed different mediators, including inflammatory cytokines that TLR4 mediates the microglial [161] oligo CpG motifs, LPS and other bacterial activation-associated interaction between amyloid beta

WebmedCentral > Review articles Page 9 of 26 WMC002410 Downloaded from http://www.webmedcentral.com on 08-Dec-2011, 05:17:29 AM

peptide and HSP70, thereby , pointing that a member the MyD88 adapter protein dependent-pathway and of the Toll-like receptor family of proteins, could also also (under certain conditions) the work in concert with FPRL1 in mediating the biological MyD88-independent pathway to propagate signals to effects of an amyloidogenic molecule( peptides). In gene targets [174, 175 ]. Aside from previously this respect, coupled with the margins of what we mentioned data, further support for this notion has presently now about the biology and activities of TLRs, been evidenced by very recent discovery, which and the findings concluding that neurodegenerative revealed that the TLR3 efficiently mediated the entry disease such as AD share various pathogenic factors of a microbial pathogen agent from the peripheral with CJD [166, 167, 168, 169] , I am tempted to blood system into the brain [176].TLR3, notably, does suggest that TLRs should have a role in mediating this not utilize the MyD88 dependent pathway for its process. The TLRs might be or might not be the cell activities. In addition to this, at the margins of what we surface receptors primarily and/or largely responsible now know about the biology and activities of TLRs in for the mediation of PrP106-126 peptide fragments health and disease states, studies designed to activities in the previously described process [162]. investigate the involvement of Toll-like receptor However, at least, TLRs, working in concert, with other signaling in the pathogenesis of a particular or any receptor proteins including FPRL1 should be specific pathological condition, using a model, implicated, in one way or the other, in this event. It whereby only MyD88-dependent pathway, for instance, may also be noteworthy, that under certain is strictly put into consideration, could hardly lead to circumstances the TLR signaling might not be required results, which could generate enough data to for particle binding or internalization. However, for categorically rule out the involvement of TLR signaling mediation of inflammatory and immune responses in the development and resolution of the concerned TLR activation and signaling are indispensable [170] pathologic condition. In the face of the above The TLRs should be directly or indirectly involved in considerations, the previous report that Toll-like the complex cascade of events that finally terminate in receptors are not involved in prion disease inflammatory responses, such as production of TNF-? pathogenesis [Prinz et al., 2003] should not be and activation of NF-?B [171, 172, 173]. Therefore, the considered as very accurate. It is now generally above observations lend further support to the notion recognized, supported by a rich vein of data [85, 93, that the TLRs may have important role in the 95, 174 ], that TLRs, working alone or in concert, can development and resolution of TSE pathology. Hence, effectively carry out their biological functions through therapeutic strategies designed to inhibit the MyD88 –dependent, and/or MyD88-independent appropriate TLRs, and FPRL1 receptors and their pathways, as well. Therefore, based on a plethora of corresponding intracellular signaling pathways may data previously described, and, coupled with a huge hold great promise for the management of TSE body of compelling data persuasively arguing in favor diseases and related cases. However, to this end, of the involvement of pathogenic microorganisms in appropriate measures should be taken to see that the driving prion diseases, [18, 101, 102, 104, 105, 106, positive biological effects of the concerned receptor 107,108 113, 177, 178 ], and strong implication of the proteins are not excessively compromised. activated microglia -and activated complement system The Variability of TLR-signaling Pathways (both represent integral components of the innate It is now generally accepted that all TLRs can utilize immune system) in TSE pathogenesis [41, 179, 180, the adapter protein MyD88 to propagate signals to 181, 182,183], I am led to strongly contend that gene targets to and generate a relatively rapid Toll-like receptors should have important role in the protective response, by activating NF kappaB or development and resolution of TSE pathology. through other routes. However, at least two Toll-like receptors (TLR3 and TLR4), as previously described, MICROGLIA ACTIVATION and PRION DISEASE can use alternative adapters such as Toll/IL-1receptor It is now largely recognized that the accumulation of resistance (TIR) domain –containing adapter inducing reactive microglia in the degenerative areas IFN-beta /TRIF) and TRIF-related adapter molecule represents the major cellular evidence pointing (TRAM); used by TLR4 than can activate responses unequivocably to the presence of neuroinflammation in different from those elicited by MyD88. Therefore, they TSE disease and other neurodegenerative disorders, (TLR3 and TLR4) utilize the adapter protein as well. Microglia are macrophage-like cells resident MyD88-independent pathway to propagate signals to within the CNS, which can perform APC and gene targets. Now, previous report that prion proinflammatory effector functions following activation. pathogenesis is unhampered in MyD88-/- mice [91] These cells are derived from bone marrow stem cells simply told us indirectly that the TLRs can utilize both and populate the CNS early during development and

WebmedCentral > Review articles Page 10 of 26 WMC002410 Downloaded from http://www.webmedcentral.com on 08-Dec-2011, 05:17:29 AM

remain in the CNS as resident macrophage population. bacterial and viral pathogens. Recent works that Microglial cells are quiescent in the CNS unable to LPS/IFN-gamma induction of gene expression utilizes perform effector and APC functions until activated by TAK1 as the major signal molecule in glial cells [195] injury or infection, and have been suggested to and Bhat and associates [196] have seriously represent the first line of defense for the CNS, which implicated TAK 1 in the induction of nitric oxide normally lacks professional APCs until they are synthase gene expression in glia cells. These findings recruited to the CNS by inflammatory stimuli [184,185]. strongly implicate Toll-like receptor protein family The neuropathology of Alzheimer`s disease and prion activities in modulating the activities of glial cells. In disease has many common features and it has been line with this, the discovery that TLR 2 and TLR4 suggested that microgial cells play a causative role in signal through TAK1, and that these two Toll-like the pathogenic cascade of neuroidegeneration in receptors are expressed in astrocytes and microglia in Alzheimer`s disease and TSE disease [ 180, 186]. vivo and potentially very strongly participate in Support for this notion has been evidenced by mediating neuroinflammatory responses to infection histological studies demonstrating that microgial cells and disease processes [ 54, 197], strongly reinforces are associated with the accumulation of abnormal , the notion that TLR-signaling participates in mediating disease-associated isoforms of prion protein, PrPSc, the activities of microglia in CNS ,and this suggests in in the central nervous system in prion disease [187]. that TAK1 may represent a potent target for The findings that fibrillar forms of amyloid –beta , or anti-inflammatory strategies against PrP peptides , stimulate microgial cells in vitro [ neuroinflammatory diseases including TSE disease. 188,189] buttress the notion that the deposition of Futhermore, microglia, which express TLR9, release amyloidogenic peptides induces microgial TNF and IL-12 when stimulated with non-methylated cell-mediated inflammatory responses that largely CpG DNA [198]. Chronic glial activation, contribute to neurodegeneration and the concomitant neurodegeneration and IL-1beta induction in rat brain cognitive decline observed in TSE disease and has been reported after administration of dsRNA, the Alzheimer’s disease.Furthermore, Microglial cells may ligand of TLR3 [199]. Now, in addition to this, be activated to produce directly neurotoxic substances interestingly, the important updates from Olson and and inflammatory mediators in experimental prion Miller [200], most persuasively buttress this notion. disease and are very likely involved in phagocytosing These investigators, based on a set of elegant series PrPSc and/ or apoptotic neurons [157, 179, 190, 191]. of experiments, demonstrated a critical role for The toxic effect of prion peptide PrP106-126 has been microglia in the innate immune response to CNS reported to require the presence of microglia, which pathogens, leading to the activation of adaptive are activated to release reactive oxygen species. immune functions, in particular, antigene presenting Therefore, PrP106-126 reduces neuronal reistance to capacity. The microglia hence represent important oxidative stress [179, 192]. The aforementioned component of both the innate and adaptive immune observations points to a critical role for activated response. Recent work by Ebert et al. [201] buttresses microglia as one of the mechanisms of this notion. Together and coupled with the fact that the neurodegeneration in prion disease. Support of this activation of microglia plays a pivotal in the notion is evidenced by the pioneering studies of pathogenesis of TSE disease, I am led to propose that Meyermann and associates [193].These authors Toll-like receptors should play important role in the concluded that the actions of activated microglia pathology of TSE disease. contribute largely to the cascade of events that finally culminate in neurodegeneration in CJD. Now, as Toll-like Receptors mediate and regulate Oxidative previously described, a wealth of scientific evidence Stress and Apoptotic Cascades has shown that TLRs engage and mediate both the A wealth of scientific data has implicated TLRs in activation and actions of microglia in CNS [54, 55, 57] mediating and regulating the pathogenic cascades of .In addition to this, TAK 1 ( TGFbeta-activated kinase oxidative stress damage [ 202, 203, 204, 205, 206, 1), is a member of the MKKK family that is increasingly 207] , and apoptotic cell death [95, 208, 209, 210, 211 being accepted to play a pivotal role in TLR signaling [ ]. Apoptosis is an active type of cell death. It differs 194]. TAK 1 ( TGFbeta-activated kinase 1) is a from necrosis in its programmed manner, complex common upstream kinase that mediates the signal regulatory mechanisms, distintive morphological transduction for inflammatory cells via changes and lack of inflammation [212, 213]. mitogen-activation protein kinase(MAPK) and Oxidative stress represents the imbalance between NF-kappaB pathways , after being activated by biochemical processes leading to production of inflammatory cytokines and engagement of TLRs by reactive oxygen species (ROS) and the cellular

WebmedCentral > Review articles Page 11 of 26 WMC002410 Downloaded from http://www.webmedcentral.com on 08-Dec-2011, 05:17:29 AM

antioxidant cascade. The consequence of this rafts in LPS involved-signaling within the macrophages. imbalance causes molecular damage that can lead to To this end , important updates by Olsson and Sundler a critical failure of biological functions and ultimately reveal that lipid rafts may play important role in TLR cell death. Hence, in line with the aforementioned, signaling [225]. These authors investigated the oxidative stress, although largely a secondary event, significance of lipid rafts in LPS signaling in emerges as an important driving force in the machrophages. They found that CD14, and MAP pathogenic cascade of events responsible for kinases (ERK2 and p38) are involved in lipid sustaining and exacerbation of the disease process in rafts-associated LPS-mediated signaling in a plethora of chronic degenerative diseases. These macrophages and that they become translocated to findings broadly implicate that toll-like receptor lipid rafts after stimulation with LPS, thereby, pointing activities-based therapeutic interventions directed at to an important role for lipid rafts in LPS-induced the key processes of these two pathogenic factors TLR4-driven signaling. The findings by Olsson and may positively influence the clinical outcome in the Sundler[225], buttress the earlier report that within the management of a plethora of pathological condiutions immune system , lipid rafts play important roles in including TSE diseases. To this end, importantly, there coordinating and mediating the signaling cascades is now strong evidence that oxidative stress [180, 214, emanating from multichain receptor complexes such 215] and apoptotic cascades [180, 216, 217, 218,219] as Fc? receptor, T cell and B cell receptors, and are key pathogenic factors involved in the pattern recognition receptors such as the TLRs [226, development and progressiong of TSE disease, and 227, 228]. Additionally, emerging evidence indicates that these features contributes strongly in facilitating that Toll-like receptor proteins may represent potential the processes of neurodegeneration in prion disease factor in regulating cholesterol metabolism [229]. This brain. Furthermore, the aforementioned obcervations, suggests a functional role for these transmembrane indeed, do not seem to argue against the involvement receptor proteins in influencing the pathogenesis of of Toll-like receptors in the pathophysiology and prion disease, for cholesterol depletion has been pathogenesis of prion disease. demonstrated to influence the conversion of PrPc into PrPc Conversion to PrPSc and Lipid Rafts PrPSc [ 230]. Furthermore, PrPc is a A key feature of prion diseases is the conversion of glycosylphosphatidylinositol (GPI) –anchored protein the normal, cellular prion protein, PrPc, into the located in lipid rafts or DRMS [231, 232]. Like other beta-sheet –rich disease-associated isoforms ,PrPSc, members of this class, many engulfing receptors and the deposition of PrPSc is thought to lead to including CD36 (a sensor of diacylglycerides:TLR-2 neurodegeneration [ 9]. The molecular mechanisms ligands [233]),CD44, and CD14 (a prominent underlying the aforemention processes are co-receptor with TLR4, and a incompletely understood. However, a convergence of glycosylphosphatidylinositol (GPI) –anchored protein) scientific evidence strongly suggest that lipid rafts are are present in lipid rafts [234], and ( GPI)-anchor is intimately involved in the process of PrPc conversion notably a prominent TLR ligand [ 235], coupled with to PrPSc [220, 221]. In this light, an important finding the fact that GPI-anchors of vasrious parasites have has reported that both PrPc and PrPSc have been been reported to be associated with a role similar to found in detergent –resistant microdomains (DRMs), that of bacterial LPS in the innate immune response, also named lipd rafts [222]. Both PrPc and PrPSc are and that despite some structural differences noted thus associastzed with DRMs in a among GPI-anchored proteins, all GPI anchors have a cholesterol-dependent. Cholesterol depletion of cells common core structure [236], I am tempted to suggest leads to decreased formation of PrPSc from PrPc. As that Toll-like Receptors might have an important role in reported by Baron et al. [ 220] the conversion of PrPs the process of PrPc to PrPSc conversion in prion to PrPSc occurs when microsomes containing are disease pathogenesis. Moreover, the ability of fused with DRMs containing PrP. Lipid rafts have been cholesterol to mudulate the conversion of PrPc to defined as liquid-ordered cholesterol and spingolipid PrPSc combined with ability of TLRs to regulate rich microdamains within the plasma membrane that cholesterol metabolism suggest that Toll-like receptor are thought to function as platforms for signaling, protein family may be a fertile avenue of research for internalization, and intracellular trafficking [ 223, 224] . the management of TSE diseases. This hypothesis They have been described to play a role in multiple underscores the importance and urgency to prototypical cascades, such as the lipopolysaccharide proactively address this subject.. pathways , and to host multiple signal proteins, Collectively, the aforementioned considerations are, including kinases and low molecular weight G-proteins. by all means, in agreement with the accepted value of Little data currently exist regarding the role of lipid scientific evidence, which generally revolves around

WebmedCentral > Review articles Page 12 of 26 WMC002410 Downloaded from http://www.webmedcentral.com on 08-Dec-2011, 05:17:29 AM

the probability and chance. Nevertheless, additionally, 245,246], can induce the maturation of DCs through in agreement with the elementary lessons in statistics, the TLR4, as well, [79, 80,]. The maturation of DCs is the probability or chance that all these findings are due an immunologically important process by which the to an indirect pathological effects or due to dendritic cells acquire an ability to present antigens coincidental circumstances related to the conundrums and to induce cellular response efficiently. and/or controversies, which prevail in the pathology of Furthermore, putting into consideration that Drosophila TSEs, seems extremely far-fetched. The sheer Toll was originally identified as essential molecule for magnitude of the insidious nature of TSEs, coupled embryonic patterning in Drosophila [247] subsequently with the fact that neither preventive measures nor shown to be of key importance in antifungal immunity long-term treatment modalities are available for the by Lemaitre B. et al. [72], and the Toll-like receptors management of this lesion, underscore the urgent are the mammalian homologue of the Drosophila Toll need to proactively address the above-mentioned receptor [ 248], it is conceivable that certain members notions by researchers, clinical investigators, and of the TLR family expressed on glia cells may be industry. implicated in both the physiological and pathophysiological functions in the brain. To this end, Conclusion(s) importantly, a huge body of scientific data has compellingly prion protein in embyronic development [ 249; 250; 251]. Therefore, it seems very difficult, if not The recent advances in our understanding of Toll-like almost impossible, to exclude the involvement of TLR receptor functions in the innate immune response receptors in the development and resolution of shed new light on how immunoinflammatory pathology in neuro- pathological conditions including responses are initiated and mediated within the central that of TSE diseases. nervous system.. It has been increasingly recognized The ability of TLR-activated APC to activate CD4+ T that Toll-like receptors (TLRs) play a major role in cells and shape a TH 1-associated immune response innate immunity to recognize specific molecular has been well described elsewhere [252; 253]. In this patterns derived from pathogens including lipids, respect, as previously described, TLRs activate protein, DNA, RNA, and also recognize endogenous multiple steps in the inflammatory reactions to ligands and small molecular synthetic compounds. eliminate the invading pathogens and subsequently These observations that TLRs are also able to sense coordinate the systemic defenses, which involves the endogenous ligands such as heat shock proteins [49], modulation of multiple dendritic cell functions and the surfacted protein A [240] and hyaluronan [80] activation of signals that are of critical importance in buttresses the “danger theory” of immune activation initiation of adaptive immune responses, unequivocally [241, 242], which holds that the induction of immunity pointing to a protective function for the innate immune requires stimulation of cells by not only non-self system. On the other hands, when the innate immune derived ligands but also the so-called “endogenous system, or a component of the innate immune system, danger signals” constituting factors released by dead is inappropriately stimulated or activated, the immune or dying cells as result of tissue damage, for instance. responses driven by this inappropriate activation may Now; quite irrespective of the evidence compellingly lead to severe consequences. In this respect, for implicating pathogenic microorganisms in driving TSE instance, excessive TLR signaling caused by microbial disease. For instance, microglial activation and infection and/or other challenges can lead to inflammatory mediators are detected in plaques in detrimental inflammation, tissue /cell damage, and TSE patients as previously described [179, 180, 182, occasionally to death. Now, CpG-containing 183], and in Alzheimer’s disease patients [ 243], as oligodeoxynucleotides (CpG-ODN) are known as well, in CNS inflammation. It is thus conceivable that strong stimulators of innate immunity by mimicking the “endogenous danger signal” exposed in the damage effects of bacterial DNA. Thus, CpG-ODNs, as incurred in the brain during the progression of the previously described, are recognized by Toll-like disease, stimulates viable glia cells through TLRs, receptor 9 (TLR9). They can act as immune adjuvants, thereby initiating inflammatory responses.These accelerating and boosting antigen-specific antibody events could well be extrapolated to the orchestrated responses by up to 500-fold. CpG motifs promote the network of events intimately involved in the production of T-helper 1 and pro-inflammatory pathogenesis of TSE diseases. For instance, heparan cytokines and induce the maturation/activation of sulfate, a products of the degradation of heparan professional antigen-presenting cells including sulfate proteoglycan, suggested by a plethora of data macrophage and dendritic cells. The therapeutic to be intimately implicated in TSE pathogenesis [ 244, importance of these products are now being studied,

WebmedCentral > Review articles Page 13 of 26 WMC002410 Downloaded from http://www.webmedcentral.com on 08-Dec-2011, 05:17:29 AM

and tested in a wide range of pathological conditions brain, which could invariably lead to a situation, where [254; 255; 256; 257; 258] including prion disease. “Horror autotoxicus” becomes commonplace. These Importantly, employloyment of this agent in the notions, therefore, strongly indicate that administration management of TSE disease by Hans Kretzschmar of CpG-ODN, under certain conditions, could also and co-workers [154] led to a protective effect on mice result or lead to premature hyperimmunity of infected with scrapie agent, consistent with the autoimmunity, Horror autotoxicus = autoimmune well-established ability of the innate immune system to reaction.”Horror autotoxicus,” a Latin expression, is a confer protection to cells. Interestingly, further studies term coined by Paul Ehrlich at the turn of the last carried out to replicate the efficacy CpG-ODN on the century to describe autoimmunity to self, or the attack prion disease [259] in a different laboratory by of “self” by immune system, which ultimately results to Heikenwalder and associates surprisingly yielded autoimmune condition. For instance, dysfunction of disastrous results. These observations [ 259], however, glutamatergic system could lead to over-expression of may not be easy to explain, for very few studies are glutamate receptors, which can in turn result to presently available on this subject with regard to prion production of physiologically active autoantibodies diseases. Nevertheless, CpG-ODN employment as [262]. These autoantibodies could be directed towards was documented by Heikenwalder and associates excitatory ionotropic glutamate receptors in the brain. [259] apparently led to negative clinical outcome, Hence, it is well-established that appropriate because, very probably, the immune system in the employment of an agent (pharmaceutical agent), in brain of the concerned TSE-infected models must most cases, result to amelioration of the concerned have been already over- stimulated. Therefore, disease state or condition with minimal side-effect. judging from the results obtained by concerned The aforementioned consideration seems to be colleagues [ 259], it might be reasonable to conclude consistent with appropriate employment of CpG-ODN that repeated application of the concerned agent to the agents. Support for this notion is evidenced by the infected models, whereby the infectious dosis, work of Zimmermann et al. [263] and that of Schetter apparently, must not have been necessarily low and associaste [198]. Additionally, and importantly, enough, could almost impossibly lead to a positive this notion has been very recently stengthened in the result. Prion protein has now been realized to have the case of prion disease by Kretzschmar and co-workers ability to induce the production of antibodies [98, 113] [154], who demonstrated positive clinical outcome as a and autoantibodies [260], and the presence of PrPSc result of CpG-ODN agent employment. The above (or PrPres), can lead to activation of the complement observations further strengthen the concept that innate system as well. In this respect, PrPres can activate the immunity may be an important player in TSE complement system, leading to production of pathology, and that TLRs are crucial receptors for the membrane attack complex (MAC) among other activation of innate immune mechanisms, and complement proteins [41]. Now, as it can be the case therefore; points to a critical role for TLRs in the under pathological condition, the complement system pathology and therapy of a wide range of diseases could be inappropriately stimulated in the process of including prion diseases. Therefore, essentially the prion disease progression, and over-stimulation of the above notions strongly argue that the previous report complement leading to sustained inappropriate [259] might not necessarily represent a negation of the production of the membrane attack complex (MAC) in well-established protective properties of the innate TSE pathogenesis. This, in turn, can initiate and immune system, nor the efficacy of CpG-ODN in the sustain the process of autodestruction of neuronal management of diseases including TSE diseases. cells and viable tissues, by host defense system, as Nevertheless, it is of importance to point out that previously described in the cases of Alzheimer`s standard conditions for effective administration of disease and Amyotrophic lateral sclerosis [141, 142], CpG- ODN as therapeutic agent have yet to be fully and, very recently, in the case of CJD by Budka and determined. The aforementioned conflicting associates [41]. Furthermore, the mere fact that the observations underscore urgent need for increased presence of PrPres could result to production of studies in this direction. To this end as recently autoantibodies; that the structure of microglia (the suggested in a closely -related case by McGeer and potent professional APCs in the CNS) could be McGeer [264], such studies could lead to less severe impaired in TSEs pathogenesis, leading to dysfunction consequences, if two major conditions are put into of APCs; and that the homeostasis of the consideration,:1) if the problems of autoimmune glutamatergic system could be significantly perturbed reaction were substantially and generally put under in TSE pathogenesis [261]; all these events possess control, 2) if appropriate measures are taken to the ability to elicit production of autoantibodies in the substantially or almost completely prevent specifically

WebmedCentral > Review articles Page 14 of 26 WMC002410 Downloaded from http://www.webmedcentral.com on 08-Dec-2011, 05:17:29 AM

the over-reactivity of the complement. Moreover, molecular underpinnings responsible for their importantly, the recent discovery disclosing that biochemical effects will allow a model to be concerted actions of tumor necrosis factor receptor 1 constructed in which the type of immune response to (TNFR1)-and TLR are may imply that antagonists of any type of infection associated with prion disease, for TNFR1-and TLR , as well as inhibitors of their instance, could be viewed as a function of many intracellular signaling pathways might be effective different determinants, including the transmembrane anti-neuroinvasion agents for the management of a protein, TLRs, the form and the nature of the microbe plethora of neurological diseases, where the process and the cytokine microenvironments. Knowledge of neuroinvasion plays a central role in the disease gained from these studies, could be employed in process. Whilst neuroinvasion is undoubtedly a targeting appropriately the pathways associated with complex process that may include other mechanisms, TLR signal-transducing activities for either inhibition or these findings by Wang et al. [174] provide important augmentation, thereby opening novel avenues in insights into the signaling pathways and processes future approaches to TSE disease therapy and other that result in neuroinvasion. It should, however, not be various pathological conditions. ruled out, that these observations [174] may bear enormous relevance to TSE pathology, and may hold Acknowledgement(s) good promise for novel therapies for a plethora of devastating neurodegenerative diseases including TSE diseases. It is reasonable to speculate that more The author; Dr. Ofodile, is exceedingly grateful to TLR proteins other than TLR3 may be involved or may Obiamaka, Ekene and Ifeanyi for their love, support, have the capacity to mediate this particular process. and understanding, and for the immense strength, Therefore, the mere fact that there are currently no which these brave and wonderful Girls gave to him preventive measures nor long-term treatment (their Father) in the last nine years, without which it modalities for TSEs, underscores the urgent need for could not have been possible for him to successfully further investigations into this particular issue. complete his investigations and bring forward this Human Toll-like receptors are transmembrane manuscript. signal-transducing receptor proteins with an The author, also, greatly acknowledged immense extracellular leucine-rich repeat domain and collegial assistance given to him by Franz Theuring, intracellular domain homologous to the IL-receptor. PhD. during the preparation of this manuscript. TLRs act as key receptors responsible not only for the detection of a variety of micobial cell-wall components Authors Contribution(s) and bacterial DNA, ds-RNA, endogenous m-RNA, endogeneous proteinaceous molecules, extracellular matrix breakdown particules, but also for the initiation OKOM NKILI-BALONWU F.C.OFODILE, PhD. and mediation of signal transduction events eventually CENTER FOR CARDIOVASCULAR RESEARCH leading to the production of various pro- inflammatory (CCR), INSTITUTE OF PHARMACOLOGY and mediators. There is no longer any doubt that TLRs are TOXICOLOGY capable of sensing microbial organisms ranging from AG: THEURING, CHARITE-UNIVERSITÄTSMEDIZIN protozoa [235] to bacteria, fungus and viruses. BERLIN Therefore; the above observations strongly strengthen HESSISCHE STR. 3-4, 10115 BERLIN, GERMANY the notion that Toll-like receptors may play an References important role in the development and resolution of TSE disease pathology. To our knowledge, this is the first work compellingly arguing in favor of the 1. Gajdusek DC. Infectious amyloid subacute involvement of TLR activities in the development and spongiform encephalopathies as transmissible resolution of TSE pathology. The message is simple; cerebral amyloidoses. In: B.N.Fields, D.M. Knipe, and the innate immune system is a complex body. What P.M. Howley (Ed.). Virology, 3rd ed. Lippincott-Raven started originally as the study of fruit flies and Publishers. Philadelphia, Pa.1996: 2851-2990 caterpillars has become the basis of our hopes for new 2. Prusiner SB.. . In : Fields BN., Knipe cures for diseases as lethal as cerebral malaria, DM.,Howley, ., Howley PM.(Eds). Virology, Third sepsis, and systemic lupus erythematosus, and Edition., Lippincoitt-Raven Publishers, Philadelpia, PA, possibly, Creutzfeldt-Jakob diseases, as well. Hence, 1991, pp.2901-2950 enhanced understanding of the Toll-like receptor 3. Unterberger U, Voigtländer T., Budka H. biology , the nature of their various ligands, and the

WebmedCentral > Review articles Page 15 of 26 WMC002410 Downloaded from http://www.webmedcentral.com on 08-Dec-2011, 05:17:29 AM

Pathogenesis of prion disease . Acta Neuropathol neurotoxicity. Nature 1996; 379:339-43. 2005; 109: 32-48 21. Lasmezas CI, Deslys J., Robain O, Jaegly A., 4. Budka H, Aguzzi A, Brown P, Brucher JM, Bugiani Beringue V., Peyrin J-M. et al. Transmission of BSE O, Gullotta F, et al. Neuropathological diagnostic Agent to Mice in the Absence of Detectable Abnormal criteria for Creutzfeldt-Jakob disease (CJD) and other Prion Protein . Science 1997; 275:402-405 human spongiform encephalopathies (prion diseases). 22. Hegde RS, Mastrianni JA, Scott MR, DeFea KA, Brain Pathol 1995 5(4):459-66. Tremblay P, Torchia M. et al. A transmembrane form 5. Chesebro B. Introduction to transmissible of the prion protein in neurodegenerative disease. spongiform encephalopathies or prion diseases. Br Science 1998; 279):827-34. Med Bull 2003; 66: 1-20 23. Kocisko DA, Come JH, Priola SA, Chesebro B, 6. Will RG, Ironside JW, Zeidler M, Cousens SN, Raymond GJ, Lansbury PT. et al. Cell-free formation Estibeiro K, Alperovitch A, Poser S, Pocchiari M, of protease-resistant prion protein. Nature 1994; Hofman A, Smith PG. A new variant of 370:471-4. Creutzfeldt-Jakob disease in the UK.. Lancet 1996 6; 24. Hill AF, Antoniou M, Collinge J.Protease-resistant 347(9006): 921-5 prion protein produced in vitro lacks detectable 7. Collinge J, Sidle KC, Meads J, Ironside J, Hill AF. infectivity. J Gen Virol 1999; 80 ( Pt 1):11-4. Molecular analysis of prion strain variation and the 25. Manuelidis L. Transmissible encephalopathies: aetiology of 'new variant' CJD. Nature 1996; 383: speculations and realities Viral Immunol 2003; 16(2): 685-90. 123-39 8. Telling GC.. Prion protein genes and prion diseases: 26. Basler K, Oesch B, Scott M, Westaway D, Walchli studies in transgenic mice. Neuropathol Appl M, Groth DF, McKinley MP, Prusiner SB, Weissmann Neurobiol. 2000; 26(3):209-20 C. Scrapie and cellular PrP isoforms are encoded by 9. Prusiner SB. The Prions. Proc Natl Acad Sci USA the same chromosomal gene. Cell 1986; 46(3):417-28 1998; 95(23): 13363-83 27. Caughey B, Race RE, Vogel M, Buchmeier MJ, 10. Weissmann C. Molecular genetics of transmissible Chesebro B.. In vitro expression in eukaryotic cells of spongiform encephalopathies. J Biol Chem. 1999; a prion protein gene cloned from scrapie-infected 274(1):3-6 mouse brain. Proc Natl Acad Sci U S A. 1988; 85(13): 11. Griffith JS. Self-replication and scrapie. Nature 4657-61 1967, 215: 1043-1044 28. Moser M, Colello RJ, Pott U, Oesch B. 12. Prusiner SB. Novel proteinaceous infectious Developmental expression of the prion protein gene in particles cause scrapie. Science 1982; 216: 136-144 glial cells.. Neuron 1995 14(3): 509-17 13. Aguzzi A, Weissmann C. Prion research: the next 29. Telling GC, Parchi P, DeArmond SJ, et al. frontiers. Nature 1997 23; 389(6653): 795-8. Evidence for the conformation of the pathologic 14. Safar J., Wille H, Itri V., et al. Eight prion strains isoform of the prion protein enciphering and have PrPSc molecules with different conformations. propagating prion diversity. Science 1996; 274: Nat Med 1998: 4:1157-65 2079-2082 15. Caughey B, Kocisko DA. Prion diseases: a 30. Bueler H, Aguzzi A, Sailer A, et al. Mice devoid of nucleic-acid accomplice? .Nature. 2003 16; 425:673-4 PrP are resistant to scrapie Cell 1993; 73 (7) : 16. Manuelidis L. Dementias, neurodegeneration, and 1339-1347 viral mechanisms of disease from the perspective of 31. Caughey B, Race RE, Ernst D, Buchmeier MJ, human transmissible encephalopathies. Ann N Y Acad Chesebro B. Prion protein biosynthesis in Sci. 1994 6; 724: 259-81 scrapie-infected and uninfected neuroblastoma cells. J 17. Hope J. The nature of the scrapie agent: the Virol 1989; 63(1):175-81 evolution of the virino Ann N Y Acad Sci. 1994; 32. Collinge J, Whittington MA, Sidle KC, Smith CJ, 724:282-9. Palmer MS, Clarke AR, Jefferys JG. . Prion protein is 18. Bastian FO, Foster JW.Spiroplasma sp. 16S rDNA necessary for normal synaptic function. . Nature 1994 in Creutzfeldt-Jakob disease and scrapie as shown by 28; 370: 295-7 PCR and DNA sequence analysis. J Neuropathol Exp 33. Sales N, Rodolfo K, Hassig R, Faucheux B, Di Neurol 2001 60(6):613-20. Giamberardino L, Moya KL: Eur J Cellular prion 19. Prusiner SB. Molecular biology of prion diseases. protein localization in rodent and primate brain. Science 1991b; 252: 1515-22 Neurosci 1998 10(7): 2464-71. 20. Brandner S, Isenmann S, Raeber A, Fischer M, 34. Brown DR, Qin K, Herms JW, Madlung A, Manson Sailer A, Kobayashi Y, Marino S. et al. Normal host J, Strome R, Fraser PE, Kruck T, von Bohlen A, prion protein necessary for scrapie-induced Schulz-Schaeffer W, Giese A, Westaway D,

WebmedCentral > Review articles Page 16 of 26 WMC002410 Downloaded from http://www.webmedcentral.com on 08-Dec-2011, 05:17:29 AM

Kretzschmar H. The cellular prion protein binds copper 47. Takeda K, Akira S. Toll-like receptors and in vivo. Nature 1997; 390(6661): 684-7 pathogen resistance. Cell Microbiol 2003; 21: 143-153 35. Brown DR Metallic prions. Biochem Soc Symp. 48, Gordon S. Pattern recognition receptors: doubling 2004; (71):193-202. up for the innate immune response. Cell 2002; 111: 36. Nishimura T, Sakudo A, Nakamura I, Lee DC, 927-930 Taniuchi Y, Saeki K, Matsumoto Y, Ogawa M, 49. Vabulas RM, Wagner H, Schild H. Heat shock Sakaguchi S, Itohara S, Onodera T. Cellular prion proteins as ligands of too-like receptors. Curr Top protein regulates intracellular hydrogen peroxide level Microbiol Immunol 2002; 270; 169-184 and prevents copper-induced apoptosis. Biochem 50. Beg AA. Endogenous ligands of Toll-like receptors: Biophys Res Commun 2004; 323(1): 218-22 implications for regulating inflammatory and immune 37. Kim BH, Lee HG, Choi JK, Kim JI, Choi EK, Carp responses. Trends Immunol 2002; 23: 509-512 RI, Kim YS . The cellular prion protein (PrPC) prevents 51. Kariko K, Ni H, Capodici J, Lamphier M, Weissman apoptotic neuronal cell death and mitochondrial D. mRNA is an endogenous ligand for Toll-like dysfunction induced by serum deprivation. Brain Res receptor 3. . J Biol Chem. 2004; 279 (13):12542-50 Mol Brain Res. 2004; 124(1): 40-50. 52. Kenward N, Hope J, Landon M, et al. Expression 38. Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, of Polyubiquitin and Heat-Shock Protein 70 Genes Cole GM, Cooper NR, Eikelenboom P, Emmerling M, Increases in the Later Stages of Disease Progression Fiebich BL, Finch CE, Frautschy S, Griffin WS, in Scrapie-infected Mouse Brain. J Neurochem 1994; Hampel H, Hull M, Landreth G, Lue L, Mrak R, 62: 1870-1877 Mackenzie IR, McGeer PL, O'Banion MK, Pachter J, 53. DebBurman SK, Raymond GR, Caughey B, et al. Pasinetti G, Plata-Salaman C, Rogers J, Rydel R, Chaperone-supervised conversion of prion protein to Shen Y, Streit W, Strohmeyer R, Tooyoma I, Van its protease-resistant form. Proc Natl Acad Sci USA Muiswinkel FL, Veerhuis R, Walker D, Webster S, 1997; 94: 13938-13943 Wegrzyniak B, Wenk G, Wyss-Coray T. Inflammation 54. Bsibsi M, Ravid R, Gveric D, van Noort JM. Broad and Alzheimer's disease. Neurobiol Aging. 2000; expression of Toll-like Receptors in Human Central 21(3): 383-421 Nervous system J Neuropathol Exp Neurol 2002; 39. Moreira PI, Smith MA, Zhu X, Honda K, Lee HG, 61(11): 1013-1021 Aliev G, Perry G. Oxidative damage and Alzheimer's 55. Schluesener HJ, Seid K, Deininger M, Schwab disease: are antioxidant therapies useful? Drug News J.Transient in vivo activation of rat brain Perspect 2005 18(1):13-9 macrophages/microglial cells and astrocytes by 40. Peyrin JM, Lasmezas CI, Haik S, et al. Microglial immunostimulatory multiple CpG oligonucleotides. J cells respond to amyloidogenic PrP peptide by the Neuroimmunol 2001; 113(1):89-94 production of inflammatory cytokines. Neuroreport 56. Hemmi H, Takeuchi O, Kawai T, Kaisho T, Sato S, 1999; 10: 723-729 Sanjo H, Matsumoto M, Hoshino K,Wagner H, Takeda 41. Kovacs GG, Gasque P, Strobel T, Lindeck-Pozza K, Akira. A Toll-like receptor recognizes bacterial DNA. E, Strohschneider M, Ironside JW. et al. Complement . Nature. 2000; 408:740-5 activation in human prion disease. Neurobiol Dis. 2004; 57. Takeshita S, Takeshita F, Haddad DE, Janabi N, 15(1):21-8 Klinman DM. Activation of microglia and astrocytes by 42. Sharief MK, Green A, Dick JPR, et al. Heightened CpG oligodeoxynucleotides. . Neuroreport 2001; intrathecal release of proinflammatory cytokines in 12(14):3029-32. Creutzfeldt-Jakob disease. Neurology 1999; 52: 1289- 58. Bowman CC, Rasley A, Tranguch SL, Marriott I. 43. Milhavet O, Lehmann S. Oxidative stress and the Cultured astrocytes express toll-like receptors for prion protein in transmissible spongiform bacterial products. Glia 2003; 43(3):281-91. encephalopathies. Brain Res Brain Res Rev 2002; 59. Lee S, Hong J, Choi SY, Oh SB, Park K, Kim JS, 38(3): 328-39 Karin M, Lee SJ.CpG oligodeoxynucleotides induce 44. Andreoletti O, Levavasseur E, Uro-Coste E, et al expression of proinflammatory cytokines and Astrocytes accumulate 4-hydroxynonenal adducts in chemokines in astrocytes: the role of c-Jun N-terminal murine scrapie and human Creutzfeldt-Jakob disease. kinase in CpG ODN-mediated NF-kappaB activation. J Neurobiol Dis 2002; 11(3): 386-393 Neuroimmunol 2004 153(1-2):50-63 45. Guentchev M, Voigtländer T, Haberler C, et al. 60. Hickey WF. Basic Principles of Immunological Evidence for oxidative stress in experimental Prion Surveillance of the Normal Central Nervous System disease. Neurobiol Dis 2000; 7: 270-273 GLIA 2001; 36: 118-124 46. Medzhitov R. Toll-like receptors and innate 61. Fearon DT, Locksley RM. The instructive role of immunity. Nat Rev Immunol 2001;1(2):135-45 the innate immunity in the acquired immune response

WebmedCentral > Review articles Page 17 of 26 WMC002410 Downloaded from http://www.webmedcentral.com on 08-Dec-2011, 05:17:29 AM

Science 1996; 272(5256): 50-3. 78. Ohashi K, Burkart V, Flohe S, Kolb H. Cutting 62. Medzhitov R, JanewayC, Jr. Innate Immunity. New edge: heat shock protein 60 is a putative endogenous Engl J Med 2000; 343: 338-344 ligand of the toll-like receptor-4 complex. J Immunol 63. Hoffmann JA, Kafatos FC, Janeway, CA., Jr. 2000; 164(2): 558-61. Ezekowitz RAB. Phylogenetic perspectives in innate 79. Johnson GB, Brunn GJ, Kodaira Y, et al, immunity. Science 1999; 284: 1313-1318 Receptor-mediated monitoring of tissue well-being via 64. Akira S, Sato S. Toll-like receptors and their detection of soluble heparin sulphate by Toll-like signaling mechanisms. Scand J Infect Dis. 2003 receptor 4 J Immunol 2002; 168: 5233-9 35(9):555-62 80. Termeer C, Benedix F, Sleeman J, et al. 65. Janeway CA, Medzhitov R.2002: “Innate innate Oligosaccharides of Hyaluronan activate dendritic cells recognition” Adv Rev Immunol 20: 197-216 via toll-like receptor 4 J Exp Med 2002; 195: 99-111 66. Pasare C, Medzhitov R. 2003 15(6):677-82. 81. Zhang D, Zhang G, Hayden MS, Greenblatt MB, Toll-like receptors: balancing host resistance with Bussey C, Flavell RA, Ghosh S. A toll-like receptor immune tolerance. Curr Opin Immunol that prevents infection by uropathogenic bacteria. 67. Takeda K, Kaisho T, and Akira S. Toll-like Science 2004; 303; 1522-6 Receptors. Annu Rev Immunol 2003 ; 21: 335-376 82. Yarovinsky F, Zhang D, Andersen JF, Bannenberg 68. Coutinho A, Poltarack A. “Innate Immunity: from GL, Serhan CN, Hayden MS, Hieny S, Sutterwala FS, lymphocyte mitogens to Toll-like receptors and back”. Flavell RA, Ghosh S, Sher A. TLR11 Activation of 2003. Curr Opin Immunol. 15: 614-619 Dendritic Cells by a Protozoan Profilin-Like Protein. 69. Janeway CA, Jr..The immune system evolved to Science 2005 Apr 28; [Epub ahead of print discriminate infectious nonself from noninfectious self. 83. Beutler B, Hoebe K, Shamel L. .Forward genetic Immunol Today 1992; 13: 11-16 dissection of afferent immunity: the role of TIR adapter 70. Medzhitov R, and Janeway CA Jr. Innate immune proteins in innate and adaptive immune responses. C recognition and control of the adaptive immune R Biol. 2004 327(6):571-80 responses. Semin Immunol 1998; 10: 351- 84. Muzio M, Ni J, Feng P, Dixit VM. IRAK (Pelle) 71. Medzhitov R, and Janesway C Jr. Innate immune family member IRAK-2 and MyD88 as proximal recognition: mechanisms and pathways, Immunol Rev mediators of IL-1 signaling. Science 1997; 278: 1612-5. 2000; 173: 89-97 85. Akira S, Takeda K. Toll-like receptor signalling. Nat 72. Lemaitre B, Nicolas E, Michaut L, Reichhart JM, Rev Immunol 2004; 4(7):499-511. Hoffmann JA. The dorsoventral regulatory gene 86. Glezer I, Rivest S Glucocorticoids: protectors of cassette spatzle/Toll/cactus controls the potent the brain during innate immune responses. antifungal response in Drosophila adults. Cell 1996 Neuroscientist 2004; 10(6):538-. 52 86(6): 973-83 87. Alexopoulou L, Holt AC, Medzhitov R, et al. 73. Poltorak A, He X, Smirnova I, Liu MY, Van Huffel Recognition of double-stranded RNA and activation of C, Du X, Birdwell D, Alejos E, Silva M, Galanos C, NF-kappaB by Toll-like receptor 3. Nature 2001; 413: Freudenberg M, Ricciardi-Castagnoli P, Layton B, 732-738 Beutler B. Defective LPS signaling in C3H/HeJ and 88. Barton GM, Medzhitov R. Toll-like receptors C57BL/10ScCr mice: mutations in Tlr4 gene. Science signaling pathways. Science 2003; 3000(5625): 1998 ; 282 : 2085-8 1524-1525 74. Tabeta K, Georgel P, Janssen E, Du X, Hoebe K, 89. Yamamoto M, Sato S, Hemmi H, Uematsu S, Crozat K, Mudd S, Shamel L, Sovath S, Goode J, Hoshino K, Kaisho T, Takeuchi O, Takeda K, Akira S.. Alexopoulou L, Flavell RA, Beutler. Toll-like receptors TRAM is specifically involved in the Toll-like receptor 9 and 3 as essential components of innate immune 4-mediated MyD88-independent signaling pathway. defense against mouse cytomegalovirus infection. B. Nat Immunol 2003; 4(11):1144-50 Proc Natl Acad Sci U S A. 2004 101(10): 3516-21 90. Fitzgerald KA, Rowe DC, Barnes BJ, Caffrey DR, 75. Beutler B, Hoebe K, Georgel P, Tabeta K, Du X. Visintin A, Latz E, Monks B, Pitha PM, Golenbock DT. Genetic analysis of innate immunity: TIR adapter LPS-TLR4 signaling to IRF-3/7 and NF-kappaB proteins in innate and adaptive immune responses. involves the toll adapters TRAM and TRIF. J. Exp Med. Microbes Infect. 2004 6(15):1374-81 2003; 198(7):1043-55 76. Medzhitov R .Toll-like receptors and innate 91. Prinz M, Heikenwalder M, Schwarz P, Takeda K, immunity. Nat Rev Immunol 2001; 1(2):135-45. Akira S, Aguzzi A. Prion pathogenesis in the absence 77. Takeuchi O, Akira S.MyD88 as a bottle neck in of Toll-like receptor signalling. EMBO Rep. 2003 Toll/IL-1 signaling. Curr Top Microbiol Immunol 2002; 4(2):195-9 270: 155-67. 92. Doherty TM, Arditi M.TB, or not TB: that is the

WebmedCentral > Review articles Page 18 of 26 WMC002410 Downloaded from http://www.webmedcentral.com on 08-Dec-2011, 05:17:29 AM

question -- does TLR signaling hold the answer? J Clin 107. Reyes JM, Hoenig EM. Intracellular spinal Invest. 2004; 114(12):1699-703. inclusions in cerebral cell processes in 93. Takeda K. Evolution and integration of innate Creutztfeldt-Jakob disease. J Neuropathol Exp Neurol immune recognition systems: the Toll-like receptors. J 1981; 40:1-8 Endotoxin Res. 2005; 11(1): 51-5 108. Liberski PP, Mori S.The Echigo-1: a 94. Palsson-McDermott EM, O'Neill LA.Signal panencephalopathic strain of Creutzfeldt-Jakob transduction by the lipopolysaccharide receptor, disease: a passage to hamsters and ultrastructural Toll-like receptor-4. Immunology 2004; 113(2):153-62. studies. Folia Neuropathol 1997; 35(4):250-4. 95. Ruckdeschel K, Pfaffinger G, Haase R, Sing A, 109. Cole RM, Tully JG, Popkin TJ, Bove Weighardt H, Hacker G, Holzmann B,Heesemann JM.Morphology, ultrastructure, and bacteriophage J.Signaling of apoptosis through TLRs critically infection of the helical mycoplasma-like organism involves toll/IL-1 receptor domain-containing adapter (Spiroplasma citri gen. nov., sp. nov.) cultured from inducing IFN-beta, but not MyD88, in bacteria-infected "stubborn" disease of citrus. J Bacteriol. 1973 murine macrophages. J Immunol 2004 173(5):3320-8 115(1):367-84 96. Watters JJ, Sommer JA, Pfeiffer ZA, Prabhu U, 110. Chastel C, Devau B, Le Goff F. et al. Mosquito Guerra AN, Bertics PJ.A differential role for the spiroplasmas from France and their ecology. Isr J Med mitogen-activated protein kinases in Sci 1987; 23(6): 683-6 lipopolysaccharide signaling: the MEK/ERK pathway is 111. Gasparich GE, Whitcomb RF, Dodge D, French not essential for nitric oxide and interleukin 1beta FE, Glass J, Williamson DL.The genus Spiroplasma production. J Biol Chem. 2002; 277(11): 9077-87 and its non-helical descendants: phylogenetic 97. Sacre SM, Andreakos E, Feldmann M, Foxwell BM. classification, correlation with phenotype and roots of Endotoxin signaling in human macrophages: signaling the Mycoplasma mycoidesclade. Int J Syst Evol via an alternate mechanism. J Endotoxin Res. 2004; Microbiol. 2004; 54(Pt 3):893-918. 10(6):445-52 112. Gasparich GE. Spiroplasmas: evolution, 98. Ebringer A, Thorpe C, Pirt J, Wilson C, and adaptation and diversity. Front Biosci. 2002 1; Cunningham P, Ettelaie C. Bovine spongiform 7:d619-40. encephalopathy: is it an autoimmune disease due to 113. Tiwana H, Wilson C, Pirt J, Cartmell W, Ebringer bacteria showing molecular mimicry with brain A .Autoantibodies to brain components and antibodies antigens? Environ Health Perspect. 1997 105 to Acinetobacter calcoaceticus are present in bovine (11):1172-4. . spongiform encephalopathy. Infect Immun. 1999; 99. Somerville RA.TSE agent strains and PrP: 67(12): 6591-5 reconciling structure and function. Trends Biochem Sci. 114. Tagliavini F, Forloni G, Colombo L. et al. 2002 27(12): 606-12. Tetracycline affects abnormal properties of synthetic 100. Eigen M.Prionics or the kinetic basis of prion PrP peptides and PrP(Sc) in vitro. J Mol Biol. 2000; diseases. Biophys Chem. 1996; 63(1): A1-18 300(5):1309-22 101. Bastian FO. Spiroplasma –like inclusion in 115. Koster T, Singh K, Zimmermann M, Gruys E. Creutzfeldt-Jakob disease. Arch Pathol Lab Med 1979; Emerging therapeutic agents for transmissible 103: 665-69 spongiform encephalopathies: areview. J Vet 102. Bastian FO, Hart MN, Cancilla PA. Additional Pharmacol Ther 2003; 26(5): 315-26 evidence of spiroplasma in Creutzfeldt-Jakob disease. 116. Murray PR, Rosenthal KS, Koyabashi GS, Pfaller Lancet 1981; 1(8221):660 MA. Medical Microbiology 1998: Third Edition. Mosby 103. Bastian FO, Purnell DM, Tully JG. –Year Book Inc. Missouri Neuropathology of spiroplasma infection in the rat 117. Mardh PA . Human respiratory tract brain. Am J Pathol 1984; 114(3):496-514. with mycoplasmas and their in vitro susceptibility to 104. Tully JG, Bastian FO, Rose DL. Localization and tetracycline and some other antibiotics. Chemotherapy persistence of spiroplasmas in an experimental brain 1975; 1: 47-57 infection in suckling rats.Ann Microbiol (Paris). 1984; 118. Seya T, Matsumoto M. . A lipoprotein family from 135A (1):111-7 Mycoplasma fermentans confers host immune 105. Bastian FO, Dash S, Garry RF.Linking chronic activation through Toll-like receptor 2. Int J Biochem wasting disease to scrapie by comparison of Cell Biol. 2002 34(8): 901-6 Spiroplasma mirum ribosomal DNA sequences. Exp 119. Nishiguchi M, Matsumoto M, Takao T, Hoshino M, Mol Pathol 2004; 77(1):49-56. Shimonishi Y, Tsuji S, Begum NA, Takeuchi O, Akira 106. Gray A, Francis RJ, Scholtz CL. Spiroplasma and S, Toyoshima K, Seya T.. Mycoplasma fermentans Creutzfeldt-Jakob disease. Lancet 1980; 2: 152 lipoprotein M161Ag-induced cell activation is mediated

WebmedCentral > Review articles Page 19 of 26 WMC002410 Downloaded from http://www.webmedcentral.com on 08-Dec-2011, 05:17:29 AM

by Toll-like receptor 2: role of N-terminal hydrophobic pnumococcus . J. Exp Med 1930; 52: 561-571 portion in its multiple functions. J Immunol 133. Cho K, Pham TN, Crivello SD, Jeong J, Green TL, 2001;166(4): 2610-6. Greenhalgh DG. Involvement of CD14 and toll-like 120. Coe JE, Race RE, Ross MJ.Serological evidence receptor 4 in the acute phase response of serum for an inflammatory response in murine scrapie. J amyloid A proteins and serum amyloid P component in Infect Dis. 2001; 183(2):185-191 the liver after burn injury. Shock. 2004 21(2):144-50 121. Volkel D, Zimmermann K, Zerr I, Lindner T. et al 134. Du Clos TW . C-reactive protein reacts with the C-reactive protein and IL-6: new marker proteins for U1 small nuclear ribonucleoprotein. . J Immunol. 1989; the diagnosis of CJD in plasma? Transfussion 2001; 143(8):2553-9.. 41(12): 1509-14 135. Kaplan MH, Volanakis JE. Interaction of 122. Gao F, Bales KR, Dodel RC, Liu J, Chen X, C-reactive protein complexes with the complement Hample H, Farlow MR, Paul SM, Du Y. NF-kappaB system. I. Consumption of human complement mediates IL-1beta-induced synthesis/release of associated with the reaction of C-reactive protein with alpha2-macroglobulin in a human glial cell line Brain pneumococcal C-polysaccharide and with the choline Res Mol Brain Res. 2002; 105(1-2): 108-14. phosphatides, lecithin and sphingomyelin. J Immunol 123. Styren SD, Kamboh MI, DeKosky ST.J. 1974 ; 112(6): 2135-47. Expression of differential immune factors in temporal 136. Volanakis JE, Complement activation by cortex and cerebellum: the role of C-reactive protein complexes. Ann NY Acad Sci. 1982; alpha-1-antichymotrypsin, apolipoprotein E, and 389: 235-250 reactive glia in the progression of Alzheimer's disease. 137. Gershov D, Kim S, Brot N, Elkon KB. C-Reactive Comp Neurol. 1998; 396(4): 511-20 protein binds to apoptotic cells, protects the cells from 124. McGeer PL, McGeer EG.. Innate immunity, local assembly of the terminal complement components, inflammation, and degenerative disease.. Sci Aging and sustains an antiinflammatory innate immune Knowledge Environ. 2002; 2002(29): re3 response: implications for systemic autoimmunity. J 125. Yasojima K, Schwab C, McGeer EG, McGeer PL. Exp Med. 2000; 192(9):1353-64 Human neurons generate C-reactive protein and 138. Torzewski M, Rist C, Mortensen RF, Zwaka TP, amyloid P: upregulation in Alzheimer's disease. Brain Bienek M, Waltenberger J, Koenig W, Schmitz G, Res. 2000; 887(1): 80-9. Hombach V, Torzewski J. C-reactive protein in the 126. McGeer EG, Yasojima K, Schwab C, McGeer PL arterial intima: role of C-reactive protein The pentraxins: possible role in Alzheimer's disease receptor-dependent monocyte recruitment in and other innate inflammatory diseases. Neurobiol atherogenesis. Arterioscler Thromb Vasc Biol. 2000; Aging. 2001; 22(6): 843-8.. 20(9): 2094-9 127. Pepys MB, Baltz ML.Acute phase proteins with 139. Zwaka TP, Hombach V, Torzewski J . C-reactive special reference to C-reactive protein and related protein-mediated low density lipoprotein uptake by proteins (pentaxins) and serum amyloid A protein. Adv macrophages: implications for atherosclerosis. Immunol 1983; 34: 141-212 Circulation 2001; 103(9): 1194-7 128. Mackiewicz A, Kushner I, Baumann H. Acute 140. Griselli M, Herbert J, Hutchinson WL, Taylor KM, phase proteins: molecular biology , biochemistry, and Sohail M, Krausz T, Pepys MB. J. C-reactive protein clinical applications; Boca Raton, FL: CRP Press. and complement are important mediators of tissue 1993; damage in acute myocardial infarction. Exp Med. 1999; 129. Van Leeuwen MA, van Rijswijk MH. Acute phase 190(12): 1733-40 proteins in the monitoring of inflammatory disorders. 141. McGeer PL, McGeer EG. Inflammation, Baillieres Clin Rheumatology 1994; 8: 531-52, autotoxicity and Alzheimer disease. Neurobiol Aging 130. Volanakis JE, Kaplan MH.. Specificity of 2001; 22(6): 799-809 C-reactive protein for choline phosphate residues of 142. McGeer P.L., McGeer, E.G. Inflammatory pneumococcal C-polysaccharide. Proc Soc Exp Biol Processes in Amyotrophic Lateral Sclerosis. Muscle Med 1971 136(2):612-4131. Chang MK, Binder CJ, Nerve 2002; 26: 459-470 Torzewski M, Witztum JL. C-reactive protein binds to 143. Szalai AJ. The antimicrobial activity of C-reactive both oxidized LDL and apoptotic cells through protein. Microbes Infect 2002; 4(2): 201-5 recognition of a common ligand: Phosphorylcholine of 144. Young B, Gleeson M, Cripps AW. C-reactive oxidized phospholipids. Proc Natl Acad Sci U S A. protein: a critical review. Pathology 1991; 23: 118-124 2002; 99(20):13043-8. 145. Abernathy TJ, Avery OT. The Occurrence during 132. Tillett WS., Francis T. Serological Reactions in acute infections of a protein not normally present in pheumonia with a non-protein somatic fraction of the blood .I. Distribution of the reactive protein in

WebmedCentral > Review articles Page 20 of 26 WMC002410 Downloaded from http://www.webmedcentral.com on 08-Dec-2011, 05:17:29 AM

patient’s sera and the effect of calcium on the cell death in prion disease. Brain Pathol 1998; 8(3): flocculation reaction with C-polysaccharide of 449-57 pneumococcus. J Exp Med. 1941; 73: 173-182 158. McGeer PL, Itagaki S, McGeer EG. Expression of 146. Du Clos TW, Mold C. The role of C-reactive the histocompatibility glycoprotein HLA-DR in protein in the resolution of bacterial infection. Curr neurological disease. Acta Neuropathol (Berl) 1988; Opin Infect Dis 2001 14(3): 289-93 76: 550-557 147. Xia D, Samols D. Transgenic mice expressing 159. McGeer PL, Kawamata T, Walker DG, et al. rabbit C-reactive protein are resistant to endotoxemia. Microglia in degenerative neurological disease. Glia Proc Natl Acad Sci U S A 1997; 94: 2575-2580 1993; 7: 84-92 148. Richardson MD., Shankland Gs, Gray CA.,. 160. Mc Geer EG, McGeer PL. The role of immune Opsonizing activity of C-ractive protein in system in Neurodegenerative Disorders. Movement phagocytodis of Aspergillus fumigatus conidia by Disorders 1997; 12(6): 855-858 human neutrophils. FEMS Microbial Immunol 1991a ;3: 161. Zhou LJ, Tedder TF. CD14+ blood monocytes 141-143 can differentiate into functionally mature CD83+ 149. Pied S, Nussler A, Pontet M, et al. C-reactive dendritic cells. Proc Natl Acad Sci 1996; 93: protein protects against preerythrocytic stages of 2588-2592 malaria Infect Immun 1989; 57: 278-282 162. Bacot SM, Lenz P, Frazier-Jessen MR, Feldman 150. Kolek MJ, Carlquist JF, Muhlestein JB, Whiting GM.Activation by prion peptide PrP106-126 induces a BM, Horne BD, Bair TL, Anderson JL.Toll-like receptor NF-kappaB-driven proinflammatory response in 4 gene Asp299Gly polymorphism is associated with human monocyte-derived dendritic cells. J Leukoc Biol. reductions in vascular inflammation, angiographic 2003; 74(1):118-25. coronary artery disease, and clinical diabetes. Am 163. Le Y, Yazawa H, Gong W, Yu Z, Ferrans VJ, Heart J. 2004; 148(6):1034-40 Murphy PM, Wang JM The neurotoxic prion peptide 151. Krieg AM, Yi AK, Matson S, Waldschmidt TJ, fragment PrP(106-126) is a chemotactic agonist for Bishop GA, Teasdale R, Koretzky GA, Klinman DM. . the G protein-coupled receptor formyl peptide CpG motifs in bacterial DNA trigger direct B-cell receptor-like 1. J Immunol 2001; 166(3): 1448-51. activation. Nature. 1995; 374(6522):546-9 164. Le Y, Murphy P, and Wang JM. Formyl-peptide 152. Jakob T, Walker PS, Krieg AM, Udey MC, Vogel receptors revisited. Trends Immunol; 2002; JC. Activation of cutaneous dendritic cells by 23(11):541-8 CpG-containing oligodeoxynucleotides: a role for 165. Kakimura J, Kitamura Y, Takata K, Umeki M, dendritic cells in the augmentation of Th1 responses Suzuki S, Shibagaki K.et al. Microglial activation and by immunostimulatory DNA. J Immunol 1998; 161(6): amyloid-beta clearance induced by exogenous 3042-9 heat-shock proteins. FASEB J. 2002; 16(6):601-3 153. Kimura Y, Sonehara K, Kuramoto E, Makino T, 166. Price DL, Borchelt DR, Sisodia SS. Alzheimer Yamamoto S, Yamamoto T, Kataoka T, Tokunaga T. disease and the prion protein disorders: amyloid Binding of oligoguanylate to scavenger receptors is beta-protein and prion protein amyloidoses. Proc. Natl. required for oligonucleotides to augment NK cell Acad. Sci. USA 1993: 90; 6381-6384; activity and induce IFN. J Biochem (Tokyo) 1994; 167. DeArmond SJ. Alzheimer’s disease and 116(5): 991-4. Creutzfeldt-Jakob disease: overlap of pathogenic 154. Sethi S, Lipford G, Wagner H, Kretzschmar H. mechanisms. Curr Opin Neurol 1993; 6, 872-881 Postexposure prophylaxis against prion disease with a 168. Silei V, Fabrizi C, Venturini G, et al. Activation of stimulator of innate immunity. Lancet 2002 ; microglial cells by PrP and beta-amyloid fragments 360(9328): 229-30. raises intracellular calcium through L-type voltage 155. De Gioia L, Selvaggini C, Ghibaudi E, Diomede L, sensitive calcium channels. Brain Res 1999; 818: Bugiani O, Forloni G, Tagliavini F, Salmona 168-170 M.Conformational polymorphism of the amyloidogenic 169. Armstrong RA, Lantos PL, Cairns NJ. The spatial and neurotoxic peptide homologous to residues patterns of prion protein deposits in Creutzfeldt-Jakob 106-126 of the prion protein. J Biol Chem. 1994; disease: comparison with beta-amyloid deposits in 269(11): 7859-62. Alzheimer’s disease. Neurosci Lett 2001; 298: 53-56 156. Bate C, Reid S, Williams A .Killing of 170. Underhill DM, Ozinsky A, Smith KD, Aderem A. prion-damaged neurons by microglia.Neuroreport Toll-like receptor-2 mediates mycobacteria-induced 2001; 12: 2589-2594 proinflammatory signaling in macrophages. Proc Natl 157. Giese A, Brown DR, Groschup MH, Feldmann C, Acad Sci U S A. 1999; 96(25):14459-63 Haist I, Kretzschmar HA.. Role of microglia in neuronal 171. Ghosh, S, et al. NF-kappa B and Rel proteins:

WebmedCentral > Review articles Page 21 of 26 WMC002410 Downloaded from http://www.webmedcentral.com on 08-Dec-2011, 05:17:29 AM

evolutionarily conserved mediators of immune G, Hoozemans JJ, Langedijk JP, Tagliavini F, responses. Ann Rev Immunol 1998; 16: 225-260 Langeveld JP, Eikelenboom Activation of human 172. Ozinsky A. et al. 2000 b. Co-operative induction microglia by fibrillar prion protein-related peptides is of pro-inflammatory signaling by Toll-like receptors. J enhanced by amyloid-associated factors SAP and C1q. Endotoxin Res 6: 393-396 Neurobiol Dis 2005; 19(1-2): 273-82 173. Zhang G, Ghosh S Toll-like receptor-mediated 184. Kim SU, de Vellis J. Microglia in health and NF-kappaB activation: a phylogenetically conserved disease. J Neurosci Res. 2005 [Epub ahead of print] paradigm in innate immunity. J Clin Invest 2001; 185. Gonzalez-Scarano F, Baltuch G. Microglia as 107:13-9 mediators of inflammatory and degenerative diseases. 174. Hoebe K, Du X, Georgel P, Janssen E, Tabeta K, Annu Rev Neurosci. 1999; 22: 219-40. Kim SO, Goode J, Lin P, Mann N, Mudd S, Crozat K, 186. Eikelenboom P, Bate C, Van Gool WA, Sovath S, Han J, Beutler B. Identification of Lps2 as a Hoozemans JJ, Rozemuller JM, Veerhuis R, Williams key transducer of MyD88-independent TIR signalling. A. Neuroinflammation in Alzheimer's disease and Nature 2003; 424 743 prion disease. Glia. 2002 40(2): 232-9 175. Marr KA, Balajee SA, Hawn TR, Ozinsky A, 187. Miyazono M, Iwaki T, Kitamoto T, Kaneko Y, Pham U, Akira S, Aderem A, Liles WC. Differential role Doh-ura K, Tateishi J. A comparative of MyD88 in macrophage-mediated responses to immunohistochemical study of Kuru and senile opportunistic fungal pathogens.. Infect Immun. 2003 plaques with a special reference to glial reactions at 71(9):5280-6. various stages of amyloid plaque formation. Am J 176. Wang T, Town T, Alexopoulou L, Anderson JF, Pathol. 1991 139(3): 589-98 Fikrig E, Flavell RA. Toll-like receptor 3 mediates West 188. Peyrin JM, Lasmezas CI, Haik S, Tagliavini F, Nile virus entry into the brain causing lethal Salmona M, Williams A, Richie D, Deslys JP, Dormont encephalitis. Nat Med. 2004; 10(12):1366-73. D. Microglial cells respond to amyloidogenic PrP 177. Wilson C, Hughes LE, Rashid T, Ebringer A, peptide by the production of inflammatory cytokines. Bansal S.. Antibodies to Acinetobacter bacteria and Neuroreport. 1999;10(4): 723-9. bovine brain peptides, measured in bovine spongiform 189. Del Bo R, Angeretti N, Lucca E, De Simoni MG, encephalopathy (BSE) in an attempt to develop an Forloni G. Reciprocal control of inflammatory cytokines, ante-mortem test. J Clin Lab Immunol. 2003;52: 23-40. IL-1 and IL-6, and beta-amyloid production in cultures. 178. Wilson C, Hughes L, Rashid T, Cunningham P, Neurosci Lett. 1995; 188(1): 70-4. Bansal S, Ebringer A, Ettelaie C. Antibodies to prion 190. Brown DR.. Microglia and prion disease. Microsc and Acinetobacter peptide sequences in bovine Res Tech. 2001; 54(2): 71-80 spongiform encephalopathy. Vet Immunol 191. Rezaie P, Lantos PL.. Microglia and the Immunopathol. 2004 98(1-2): 1-7. pathogenesis of spongiform encephalopathies. Brain 179. Brown DR., Schmidt B., Kretschmar HA. Role of Res Brain Res Rev. 2001; 35(1): 55-72. microglia and host prion protein in neurotoxicity of 192. Brown DR, Schulz-Schaeffer WJ, Schmidt B, prion protein fragment . Nature 1996; 380: 345 -347. Kretzschmar HA.. Prion protein-deficient cells show 180. Van Everbroeck B, Dobbeleir I, De Waele M, De altered response to oxidative stress due to decreased Leenheir E, Lubke U, Martin JJ, Cras P.. Extracellular SOD-1 activity. Exp Neurol. 1997; 146(1):104-12 protein deposition correlates with glial activation and 193. Muhleisen H, Gehrmann J, Meyermann R. oxidative stress in Creutzfeldt-Jakob and Alzheimer's Reactive microglia in Creutzfeldt-Jakob disease. disease. Acta Neuropathol (Berl) 2004; Neuropathol Appl Neurobiol. 1995; 21(6): 505-17 108(3):194-200. 194. Irie T, Muta T, Takeshige K. TAK1 mediates an 181. Mabbott NA, Bruce ME, Botto M, Walport MJ, activation signal from toll-like receptor(s) to nuclear Pepys MB.. Temporary depletion of complement factor-kappaB in lipopolysaccharide-stimulated component C3 or genetic deficiency of C1q macrophages FEBS Lett. 2000; 467(2-3): 160-4. significantly delays onset of scrapie. Nat Med. 195. Shuto T, Xu H, Wang B, Han J, Kai H, Gu XX, 2001;7(4): 485-7 Murphy TF, Lim DJ, Li JD. Activation of NF-kappa B 182. Guiroy DC, Wakayama I, Liberski PP, Gajdusek by nontypeable Hemophilus influenzae is mediated by DC. Relationship of microglia and scrapie toll-like receptor 2-TAK1-dependent NIK-IKK alpha amyloid-immunoreactive plaques in kuru, /beta-I kappa B alpha and MKK3/6-p38 MAP kinase Creutzfeldt-Jakob disease and Gerstmann-Straussler signaling pathways in epithelial cells. Proc Natl Acad syndrome. Acta Neuropathol (Berl) 1994; 87(5): Sci U S A. 2001; 98(15): 8774-9 526-30. 196. Bhat NR, Shen Q, Fan F.. TAK1-mediated 183. Veerhuis R, Boshuizen RS, Morbin M, Mazzoleni induction of nitric oxide synthase gene expression in

WebmedCentral > Review articles Page 22 of 26 WMC002410 Downloaded from http://www.webmedcentral.com on 08-Dec-2011, 05:17:29 AM

glial cells. J Neurochem. 2003; 87(1): 238-47 remodeling. Curr Opin Lipidol. 2004 ; 15(5): 515-21. 197. Zekki H, Feinstein DL, Rivest S. The clinical 209. Kaiser WJ, Offermann MK. Apoptosis induced by course of experimental autoimmune encephalomyelitis the toll-like receptor adaptor TRIF is dependent on its is associated with a profound and sustained receptor interacting protein homotypic interaction motif. transcriptional activation of the genes encoding toll-like J Immunol. 2005; 174(8): 4942-52 receptor 2 and CD14 in the mouse CNS. Brain Pathol. 210. Fischer SF, Rehm M, Bauer A, Hofling F, 2002 12(3): 308-19. . Kirschnek S, Rutz M, Bauer S, Wagner H, Hacker G. 198. Dalpke AH, Schafer MK, Frey M, Zimmermann S, Toll-like receptor 9 signaling can sensitize fibroblasts Tebbe J, Weihe E, Heeg K. Immunostimulatory for apoptosis. Immunol Lett. 2005; 97(1):115-22. CpG-DNA activates murine microglia. J Immunol. 211. Rasschaert J, Ladriere L, Urbain M, Dogusan Z, 2002;168(10): 4854-63. Katabua B, Sato S, Akira S, Gysemans C, Mathieu C, 199. Melton LM, Keith AB, Davis S, Oakley AE, Eizirik DL. Toll-like receptor 3 and STAT-1 contribute Edwardson JA, Morris CM. Chronic glial activation, for dsRNA+IFN-gamma -induced apoptosis in primary neurodegeneration, and APP immunoreactive deposits pancreatic beta -cells. J Biol Chem. 2005; [Epub following acute administration of double-stranded RNA. ahead of print] Glia. 2003 ; 44(1): 1-12. 212. Wyllie AH, Beattie GJ, Hargreaves Ad. Chromatin 200. Olson JK, Miller SD. Microglia initiate central Changes in apoptosis. Histochem J 1981; 132: nervous system innate and adaptive immune 681-692 responses through multiple TLRs. J Immunol. 2004; 213. Graham SH, Chen J. Programmed cell death in 173(6): 3916-24. cerebral ischemia. J Cereb Blood Flow Metab. 2001; 201. Ebert S, Gerber J, Bader S, Muhlhauser F, 21(2): 99-109. Brechtel K, Mitchell TJ, Nau R. . Dose-dependent 214. Arlt S, Kontush A, Zerr I, Buhmann C, Jacobi C, activation of microglial cells by Toll-like receptor Schroter A, Poser S, Beisiegel U.. Increased lipid agonists alone and in combination. J Neuroimmunol. peroxidation in cerebrospinal fluid and plasma from 2005; 159(1-2): 87-96 patients with Creutzfeldt-Jakob disease. Neurobiol Dis. 202. Asehnoune K, Strassheim D, Mitra S, Kim JY, 2002 ;10(2): 150-6 Abraham E.. Involvement of reactive oxygen species 215. Thackray AM, Knight R, Haswell SJ, Bujdoso R, in Toll-like receptor 4-dependent activation of Brown DR.Metal imbalance and compromised NF-kappa B. J Immunol. 2004;172(4): 2522-9 antioxidant function are early changes in prion disease. 203. Frantz S, Kelly RA, Bourcier T.Role of TLR-2 in Bi ochem J. 2002; 362(Pt 1): 253-8 the activation of nuclear factor kappaB by oxidative 216. Kim BH, Lee HG, Choi JK, Kim JI, Choi EK, Carp stress in cardiac myocytes. J Biol Chem. 2001; 276(7): RI, Kim YS.The cellular prion protein (PrPC) prevents 5197-203 apoptotic neuronal cell death and mitochondrial 204. Suliman HB, Welty-Wolf KE, Carraway MS, dysfunction induced by serum deprivation. Brain Res Schwartz DA, Hollingsworth JW, Piantadosi CA. Mol Brain Res. 2004;124(1): 40-50. Toll-like receptor 4 mediates mitochondrial DNA 217. Castilla J, Hetz C, Soto C.. Molecular damage and biogenic responses after heat-inactivated mechanisms of neurotoxicity of pathological prion E. coli. FASEB J. 2005; [Epub ahead of print] protein. Curr Mol Med. 2004; 4(4): 397-403 205. Park HS, Jung HY, Park EY, Kim J, Lee WJ, Bae 218. Schatzl HM, Laszlo L, Holtzman DM, Tatzelt J, YS. Cutting edge: direct interaction of TLR4 with DeArmond SJ, Weiner RI, Mobley WC, Prusiner SB. A NAD(P)H oxidase 4 isozyme is essential for hypothalamic neuronal cell line persistently infected lipopolysaccharide-induced production of reactive with scrapie prions exhibits apoptosis. . J Virol. 1997 oxygen species and activation of NF-kappa B. J 71(11): 8821-31 Immunol. 2004; 173(6): 3589-93 219. Van Everbroeck B, Dewulf E, Pals P, Lubke U, 206. Fan J, Frey RS, Malik AB. TLR4 signaling Martin JJ, Cras P. The role of cytokines, astrocytes, induces TLR2 expression in endothelial cells via microglia and apoptosis in Creutzfeldt-Jakob disease. neutrophil NADPH oxidase. J Clin Invest. Neurobiol Aging. 2002 ;23(1): 59-64. 2003;112(8):1234-43. 220. Baron GS, Wehrly K, Dorward DW, Chesebro B, 207. Gantner BN, Simmons RM, Canavera SJ, Akira S, Caughey B Conversion of raft associated prion protein Underhill DM.. Collaborative induction of inflammatory to the protease-resistant state requires insertion of responses by dectin-1 and Toll-like receptor 2. J Exp PrP-res (PrP(Sc)) into contiguous membranes. EMBO Med. 2003;197(9):1107-17 J. 2002; 21(5): 1031-40.. 208. Vink A, de Kleijn DP, Pasterkamp. Functional role 221. Taraboulos A, Scott M, Semenov A, Avrahami D, for toll-like receptors in atherosclerosis and arterial Laszlo L, Prusiner SB. Cholesterol depletion and

WebmedCentral > Review articles Page 23 of 26 WMC002410 Downloaded from http://www.webmedcentral.com on 08-Dec-2011, 05:17:29 AM

modification of COOH-terminal targeting sequence of and roles for the sugars. Biochemistry. 2001; 40(13): the prion protein inhibit formation of the scrapie 3759-66. isoform. J Cell Biol. 1995;129(1): 121-32. 235. Stahl N, Borchelt DR, Hsiao K, Prusiner SB. 222. Naslavsky N, Stein R, Yanai A, Friedlander G, Scrapie prion protein contains a phosphatidylinositol Taraboulos A. .Characterization of detergent-insoluble glycolipid. Cell. 1987; 51(2): 229-40. complexes containing the cellular prion protein and its 236. Hoebe K, Georgel P, Rutschmann S, Du X, Mudd scrapie isoform. J Biol Chem. 1997; 272(10): 6324-31 S, Crozat K, Sovath S, Shamel L, Hartung T, 223. Simons K, Toomre D.. Lipid rafts and signal Zahringer U, Beutler B. . CD36 is a sensor of transduction. Nat Rev Mol Cell Biol. 2000;1(1): 31-9. diacylglycerides. Nature. 2005; 433(7025): 523-7. 224. London E, Brown DA..Insolubility of lipids in triton 237. Chimini G. Engulfing by lipids: a matter of taste? X-100: physical origin and relationship to Cell Death Differ. 2001; 8(6): 545-8 sphingolipid/cholesterol membrane domains (rafts). 238. Gazzinelli RT, Ropert C, Campos MA.Role of the Biochim Biophys Acta. 2000; 1508 (1-2): 182-95. Toll/interleukin-1 receptor signaling pathway in host 225. Olsson S, Sundler R. The role of lipid rafts in resistance and pathogenesis during infection with LPS-induced signaling in a macrophage cell line. Mol protozoan parasites. Immunol Rev 2004; 201: 9-25 Immunol. 2005 May 16;( ahead of Print) 239. Ferguson MA. The structure, biosynthesis and 226. Miceli MC, Moran M, Chung CD, Patel VP. functions oglycosylphosphatidylinositol anchors, and Co-stimulation and counter-stimulation: lipid raft the contributions of trypanosome research. J Cell Sci. clustering controls TCR signaling and functional 1999;112 ( Pt 17): 2799-809. outcomes. Semin Immunol. 2001 13(2):115-28 240. Guillot L, Balloy V, McCormack FX, Golenbock 227. Pierce SK. Lipid rafts and B-cell activation. Nat DT, Chignard M, Si-Tahar M.Cutting edge: the Rev Immunol. 2002; 2(2): 96-105 immunostimulatory activity of the lung surfactant 228. Triantafilou M, Miyake K, Golenbock DT, protein-A involves Toll-like receptor 4. J Immunol 2002; Triantafilou K.. Mediators of innate immune recognition 168(12): 5989-92 of bacteria concentrate in lipid rafts and facilitate 241. Matzinger P. The Danger Model: a renewed lipopolysaccharide-induced cell activation. J Cell Sci. sense of self. Science 2002; 296: 301-305; 2002; 115(Pt 12): 2603-11 242. Matzinger P. Tolerance, danger, and the 229. Parker LC, Whyte MK, Vogel SN, Dower SK, extended family. Annu Rev Immunol. 1994;12 Sabroe I. Toll-like receptor (TLR)2 and TLR4 agonists :991-1045 regulate CCR expression in human monocytic cells. J 243. Smiley ST, King JA, Hancock WW. Fibrinogen Immunol. 2004 172(8): 4977-86 stimulates macrophage chemokine secretion through 230. Castrillo A, Joseph SB, Vaidya SA, Haberland M, toll-like receptor 4.. Immunol 2001; 167(5): 2887-94. Fogelman AM, Cheng G, Tontonoz P. Crosstalk 244. Wong C, Xiong LW, Horiuchi M, Raymond L, between LXR and toll-like receptor signaling mediates Wehrly K, Chesebro B, Caughey B. Sulfated glycans bacterial and viral antagonism of cholesterol and elevated temperature stimulate PrP metabolism. Mol Cell. 2003;12(4): 805-16. (Sc)-dependent cell-free formation of 231. Zareparsi S, Buraczynska M, Branham KE, Shah protease-resistant prion protein. EMBO J. 2001; 20(3): S, Eng D, Li M, Pawar H, Yashar BM, Moroi SE, 377-86 Lichter PR, Petty HR, Richards JE, Abecasis GR, 245. Gabizon R, Meiner Z, Halimi M, Ben-Sasson SA. Elner VM, Swaroop A.. Toll-like receptor 4 variant Heparin-like molecules bind differentially to D299G is associated with susceptibility to age-related prion-proteins and change their intracellular metabolic macular degeneration. Hum Mol Genet. 2005; fate.. J Cell Physiol. 1993 ; 157(2): 319-25 14(11):1449-55 246. Diaz-Nido J, Wandosell F, Avila J. 232. Cuschieri J.. Implications of lipid raft Glycosaminoglycans and beta-amyloid, prion and tau disintegration: enhanced anti-inflammatory peptides in neurodegenerative diseases. Peptides macrophage phenotype. Surgery. 2004; 136(2): 2002; 23(7):1323-32. 169-75 247. Hashimoto C, Hudson KL, Anderson KV... The 233. Sarnataro D, Campana V, Paladino S, Toll gene of Drosophila, required for dorsal-ventral Stornaiuolo M, Nitsch L, Zurzolo C. PrP(C) association embryonic polarity, appears to encode a with lipid rafts in the early secretory pathway stabilizes transmembrane protein. Cell 1988; 52(2): 269-79 its cellular conformation. Mol Biol Cell. 2004;15(9): 248. Medzhitov R, Preston-Hurlburt P, Janeway CA 4031-42. Jr... A human homologue of the Drosophila Toll protein 234. Rudd PM, Wormald MR, Wing DR, Prusiner SB, signals activation of adaptive immunity. Nature 1997; Dwek RA.. Prion glycoprotein: structure, dynamics, 388: 394-7

WebmedCentral > Review articles Page 24 of 26 WMC002410 Downloaded from http://www.webmedcentral.com on 08-Dec-2011, 05:17:29 AM

249. Santuccione A, Sytnyk V, Leshchyns'ka I, oligodeoxynucleotides trigger protective and curative Schachner M. Prion protein recruits its neuronal Th1 responses in lethal murine leishmaniasis. J receptor NCAM to lipid rafts to activate p59fyn and to Immunol 1998; 160(8): 3627-30 enhance neurite outgrowth. J Cell Biol. 2005; 169(2): 264. McGeer PL, McGeer E. Is there a future for 341-54. vaccination as a treatment for Alzheimer's disease? 250. Cotto E, Andre M, Forgue J, Fleury HJ, Babin PJ. Neurobiol Aging. 2003; 24(3): 391-5 Molecular characterization, phylogenetic relationships, and developmental expression patterns of prion genes in zebrafish (Danio rerio). FEBS J. 2005; 272(2): 500-13 251. Miele G, Alejo Blanco AR, Baybutt H, Horvat S, Manson J, Clinton M.Embryonic activation and developmental expression of the murine prion protein gene. Gene Expr. 2003;11(1):1-12. 252. Akira S, Takeda K, Kaisho T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol. 2001; 2(8): 675-80 253. Kaisho T, Akira S. Regulation of dendritic cell functions through toll-like receptors. Curr Mol Med 2003; 3(8): 759-71 254. Krieg AM.. CpG motifs: the active ingredient in bacterial extracts? Nat Med 2003; 9(7): 831-5. 255. Jiang ZH, Koganty RR. Synthetic vaccines: the role of adjuvants in immune targeting. Curr Med Chem 2003; 10(15):1423-39. 256. Uhlmann E, Vollmer J... Recent advances in the development of immunostimulatory oligonucleotides. Curr Opin Drug Discov Devel 2003; 6(2): 204-17 257. Schetter C, Vollmer J. .. Toll-like receptors involved in the response to microbial pathogens: development of agonists for toll-like receptor 9. Curr Opin Drug Discov Devel. 2004; 7(2): 204-10 258. Klinman DM. Use of CpG oligodeoxynucleotides as immunoprotective agents. Expert Opin Biol Ther 2004 ; 4(6): 937-46 259. Heikenwalder M, Polymenidou M, Junt T, Sigurdson C, Wagner H, Akira S, Zinkernagel R, Aguzzi A.Lymphoid follicle destruction and immunosuppression after repeated CpG oligodeoxynucleotide administration. Nat Med 2004; 10(2): 187-92 260. Cossu G, Melis M, Molari A, Pinna L, Ferrigno P, Melis G. et al.Creutzfeldt-Jakob disease associated with high titer of antithyroid autoantibodies: case report and literature review. Neurol Sci. 2003; 24(3): 138-40 261. Diez M, DeArmond SJ, Groth D, Prusiner SB, Hokfelt T. Decreased MK-801 binding in discrete hippocampal regions of prion-infected mice.. Neurobiol Dis. 2001 8(4): 692-9 262. Gahring LC, Rogers SW. Autoimmunity to glutamate receptors in the central nervous system. Crit Rev Immunol 2002; 22(4): 295-316 263. Zimmermann S, Egeter O, Hausmann S, Lipford GB, Rocken M, Wagner H, Heeg K. CpG

WebmedCentral > Review articles Page 25 of 26 WMC002410 Downloaded from http://www.webmedcentral.com on 08-Dec-2011, 05:17:29 AM

Disclaimer

This article has been downloaded from WebmedCentral. With our unique author driven post publication peer review, contents posted on this web portal do not undergo any prepublication peer or editorial review. It is completely the responsibility of the authors to ensure not only scientific and ethical standards of the manuscript but also its grammatical accuracy. Authors must ensure that they obtain all the necessary permissions before submitting any information that requires obtaining a consent or approval from a third party. Authors should also ensure not to submit any information which they do not have the copyright of or of which they have transferred the copyrights to a third party. Contents on WebmedCentral are purely for biomedical researchers and scientists. They are not meant to cater to the needs of an individual patient. The web portal or any content(s) therein is neither designed to support, nor replace, the relationship that exists between a patient/site visitor and his/her physician. Your use of the WebmedCentral site and its contents is entirely at your own risk. We do not take any responsibility for any harm that you may suffer or inflict on a third person by following the contents of this website.

WebmedCentral > Review articles Page 26 of 26