Mycobacterial Signaling Through Toll-Like Receptors

MINI REVIEW ARTICLE published: 23 November 2012 CELLULAR AND INFECTION MICROBIOLOGY doi: 10.3389/fcimb.2012.00145 Mycobacterial signaling through toll-like receptors

Joyoti Basu 1, Dong-Min Shin 2 and Eun-Kyeong Jo 2*

1 Department of Chemistry, Bose Institute, Kolkata, India 2 Department of Microbiology and Infection Signaling Network Research Center, Chungnam National University School of Medicine, Daejeon, South Korea

Edited by: Studies over the past decade have helped to decipher molecular networks dependent Nelson Gekara, Umea University, on Toll-like receptor (TLR) signaling, in mycobacteria-infected macrophages. Stimulation Sweden of TLRs by mycobacteria and their antigenic components rapidly induces intracellular Reviewed by: signaling cascades involved in the activation of nuclear factor-κB and mitogen-activated Maximiliano G. Gutierrez, Medical Research Council- National Institute protein kinase pathways, which play important roles in orchestrating proinﬂammatory for Medical Research, UK responses and innate defense through generation of a variety of antimicrobial effector Javeed Ali Shah, University of molecules. Recent studies have provided evidence that mycobacterial TLR-signaling cross Washington, USA talks with other intracellular antimicrobial innate pathways, the autophagy process and *Correspondence: functional vitamin D receptor (VDR) signaling. In this article we describe recent advances Eun-Kyeong Jo, Department of Microbiology and Infection Signaling in the recognition, responses, and regulation of mycobacterial signaling through TLRs. Network Research Center, Chungnam National University Keywords: mycobacteria, vitamin D, autophagy, antimicrobial peptides, innate immunity School of Medicine, 301-747, Daejeon, South Korea. e-mail: [email protected]

INTRODUCTION intracellular microbes, including Mtb (Deretic, 2012; Mintern Tuberculosis remains a serious health problem worldwide, caus- and Villadangos, 2012). Pathogenic mycobacteria utilize a unique ing an alarming two million deaths annually (WHO, 2010). strategy to survive within macrophages. They have developed One-third of the global population is latently infected with tactics to escape from host autophagic process. They also Mycobacterium tuberculosis (Mtb). In this state, healthy immune- expose multiple ligands that are recognized by host TLRs. An competent individuals are able to combat infection by mounting understanding of the complex mechanisms involved in this of an effective immune response (Huynh et al., 2011). When the hide-and-seek game (host-pathogen interaction) is required immune system is compromised, the bacteria are capable of repli- for development of novel intervention strategies to combat cating, disseminating, and causing a progressive infectious disease tuberculosis. (Huynh et al., 2011). Thus, appropriate and efficient mounting In this Review, we focus on emerging data showing that of host immune responses are required for controlling tuber- mycobacteria and their ligands activate or modulate TLR signal- culosis infection. Protective immunity to mycobacteria mainly ing pathways. Specifically, we discuss the mechanisms by which requires an interplay between innate immune responses and TLR signaling regulates the initiation and progression of innate Th1-dependent cellular immune responses, which cooperatively immune responses, and eradication of intracellular mycobacteria contribute to clear the major human pathogen, Mtb (Zuñiga through cooperation with autophagy and VDR signaling pathway. et al., 2012). During infection of macrophages, Mtb and its components OVERVIEW OF TLRs IN MYCOBACTERIAL INFECTION encounters innate immunity, which operates through a vari- Mtb primarily invades the lung alveoli via inhalation and alve- ety of germline-encoded pattern recognition receptors including olar macrophages are the principal cell types infected by this Toll-like receptors (TLRs) for recognition of various molecu- pathogen (Huynh et al., 2011). When Mtb are internalized by lar patterns of mycobacteria (Jo et al., 2007; Natarajan et al., alveolar macrophages or other innate cells, they encounter a vari- 2011). The innate immune response triggered by engage- ety of intracellular innate receptors including TLRs. So far, there ment of TLRs, involves recruitment of cytoplasmic adap- is evidence that mycobacterial components are engaged by TLR2 tor proteins and intracellular signaling molecules resulting in in association with TLR1/TLR6, by TLR4, or by TLR9 (which rec- phagosome maturation and the synthesis of pro-inflammatory ognizes Mtb DNA) (Doherty and Arditi, 2004; Jo et al., 2007). cytokines (Sundaramurthy and Pieters, 2007; Natarajan et al., Earlier in vivo studies showed somewhat discordant results in sus- 2011). Antimicrobial responses through TLR-dependent trigger- ceptibility of mice deficient in several TLR-related genes, including of intracellular signaling cascades, involves the activation ing TLR2, TLR4, TLR6, or MyD88, in Mtb infection (Doherty of nuclear factor (NF)-κB in murine macrophages and vitamin and Arditi, 2004; Quesniaux et al., 2004). It was also reported that D receptor (VDR) signaling in human monocytes/macrophages TLR2/4/9-deficient mice have no apparent difference in activation (Sundaramurthy and Pieters, 2007; Jo, 2010; Yuk et al., of antigen-specific T cells, and production of pro-inflammatory 2012). Recent studies have also highlighted that the autophagy cytokines and interferon (IFN)-γ, when compared with wild-type pathway is critically involved in degradation/elimination of mice (Hölscher et al., 2008). The controversial results might be

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due to differences in Mtb strains used, doses of infection, differ- MAPK-dependent signaling, it may also be noted that the tran- ences in genetic backgrounds, etc. The detailed description about scription factor nuclear factor of activated T cells 5 (NFAT5) can the in vivo role of TLRs in mycobacterial infection is summa- be activated by TLR signaling induced by Mtb stimulation, and rized in excellent earlier reviews by Stenger and Modiln (2002); the co-infection of HIV-1 in tuberculosis accelerates an increase Doherty and Arditi (2004); and Quesniaux et al. (2004). However, of viral load through expression of NFAT5 (Ranjbar et al., 2012). the exact roles and regulatory mechanisms by which TLRs affect Recent reports have highlighted that other cells such as alveolar innate immunity and antimicrobial responses have not been fully epithelial cells play an important role in innate defense to produce characterized. the chemokine CCL2 and also in the pathogenesis of mycobacte- Numerous studies have revealed that TLR2 is involved in the rial infection (Chuquimia et al., 2012). Additionally, mast cells innate recognition and responses in innate immune cells such are activated by mycobacterial LAM to induce the generation of as macrophages and dendritic cells of a variety of mycobacte- cysteinyl leukotriene through TLR2-NF-κB-dependent signaling rial cell wall antigens including 19-kDa mycobacterial lipoprotein, (Ba¸bolewska et al., 2012). Together, these studies suggest that glycolipids like lipoarabinomannan (LAM), LM, 38-kDa antigen, TLRs have a crucial role in the host immune responses against LprG lipoprotein, phosphatidylinositol mannoside (PIM), tria- mycobacterial infection and that they are involved in not only cylated (TLR2/TLR1), or diacylated (TLR2/TLR6) lipoproteins immune cells but also other cells. These findings have been sum- [reviewed in Jo et al. (2007); Kleinnijenhuis et al. (2011)]. TLR4 marized in Figure 1. In this context, it is pertinent to note that is activated by heat shock protein 60/65 and 38-kDa antigen, while, to the best of our knowledge, there is no detailed report whereas TLR9 recognizes unmethylated CpG motifs of mycobac- on the temporal dynamics of NF-κB activation during infection, terial DNA [reviewed by Jo et al. (2007); Kleinnijenhuis et al. our (Basu laboratory) unpublished observations from ex vivo (2011)]. Stimulation of TLRs by mycobacterial ligands leads to an experiments using Mtb-infected macrophages, indicate that the initiation of intracellular signaling cascades culminating in proin- upregulation of NF-κB dampening molecules such as TNFAIP3 flammatory cytokine generation in macrophages and dendritic (A20) occurs as early as 24 h post-infection. It is obvious that Mtb cells through activation of NF-κBandMAPKpathways(Jo et al., elicits inflammation-dampening signals in macrophages which 2007, summarized in Figure 1). Along with canonical NF-κBand would favor its survival.

FIGURE 1 | A schematic model for TLRs activation by diverse (TDM), phosphatidylinositol mannoside (PIM) activate TLR2/1 or 6, whereas mycobacterial antigens. TLRs are involved in the innate recognition and TLR4 recognizes heat shock protein (HSP) 60/65 and 38-kDa antigen. TLR responses in innate immune cells to numerous mycobacterial antigens. activation by mycobacterial antigens leads an intracellular signaling pathway Some mycobacterial antigens including LpqH, lipoarabinomannan (LAM), that culminates in the production of proinﬂammatory in macrophages and lipomannan (LM), 38-kDa antigen, LprG, LprA, PhoS1, trehalose dimycolate dendritic cells through MAPK and NF-κB pathways.

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TLRs SIGNALING BY MYCOBACTERIAL COMPONENTS Yet another effecter of proinflammatory cytokine produc- Many previous studies have reported that mycobacterial compo- tion is trehalose dimycolate (TDM). TDM has been reported nents are involved in innate recognition and responses through to be tethered to several receptors, including TLR2, the class TLR signaling (Basu et al., 2007; Pathak et al., 2009; Bansal A scavenger receptor MARCO, Fc receptor-γ (FcRγ), and et al., 2010, 2011; Heo et al., 2011; Byun et al., 2012a,b). macrophage-inducible C-type lectin (Mincle) (Bowdish et al., Antigens of the PE_PGRS family, namely, PE_PGRS 17 (Rv0978c) 2009; Ishikawa et al., 2009; Werninghaus et al., 2009). TDM and PE_PGRS 11 (Rv0754), recognize TLR2 to induce matura- triggers MARCO/TLR2/CD14-dependent signaling to produce tion and activation of human dendritic cells, and enhance the proinflammatory cytokines (Bowdish et al., 2009). In addition ability of dendritic cells to stimulate CD4(+) T cells (Bansal to TLR2-dependent signaling, TDMs also activate macrophages et al., 2010). These PE_PGRS proteins activate dendritic cells and dendritic cells via FcRγ-Syk-Card9 pathway (Werninghaus through ERK1/2 and p38 MAPK signaling pathways. Basu et al., 2009). Mincle, which is one of the C-type lectin recep- et al. have shown that PE_PGRS 33 signals through TLR2 to tors expressed in macrophages subjected to several types of stress release TNF-α to induce apoptosis of macrophages (Basu et al., (Matsumoto et al., 1999), is an essential receptor for TDM- 2007). dependent inflammatory responses, nitric oxide synthesis, and Other Mtb proteins have been shown to influence dendritic granuloma formation (Ishikawa et al., 2009). TDM receptors are cell function. Rv0462 (lipoamide dehydrogenase C), Rv0315, associated with partial protection against Mtb infection (Bowdish and Rv0577 (Mtb-restricted secretory protein involved in the et al., 2009; Ishikawa et al., 2009; Werninghaus et al., 2009). methylglyoxal detoxification pathway) induce dendritic cell mat- Recent work by Bansal et al. (2011) suggests that upon infec- uration and activation leading to increased expression of cos- tion with M. bovis bacille Calmette-Guérin (BCG), TLR2 signal- timulatory molecules (CD80, CD86, and class II MHC) and ing activates Wnt-β-catenin signaling. The authors suggest that proinflammatory cytokines (TNF-α,IL-1β, IL-6, and IL-12), TLR2 integrates Wnt-β-catenin signaling to modulate a battery and potentiate the Th1 immune response (Heo et al., 2011; of genes associated with T(Reg) cell lineage commitment. At Byun et al., 2012a,b). These findings have been summarized in low MOIs, Mtb-triggered macrophage apoptosis depends on a Figure 2. TLR2 signaling cascade associated with ASK1/p38 MAPK- and

FIGURE 2 | A schematic diagram for mechanisms of dendritic cell apoptosis in macrophages. Others (e.g., Rv0462, Rv0315, Rv0577,and maturation/activation to stimulate T cells by mycobacterial antigens. PE_PGRS 17/11) increase expression of costimulatory molecules (CD80, PE_PGRS proteins activate dendritic cells through TLR2-MAPK-NF-κB CD86, and class II MHC) and proinﬂammatory cytokines (TNF-α,IL-1β,IL-6, signaling pathways. PE_PGRS 33-induced TNF-α by dendritic cells induces and IL-12), leading to Th1 immune responses.

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c-Abl-dependent phosphorylation of c-FLIP and its degradation, cells. Activation of autophagy has a critical effector role in innate leading to caspase 8 activation (Kundu et al., 2009). immune responses such as enhancement of phagosomal matura- TLR-dependent NF-κB signaling and MAPK pathways con- tion and coordination of the innate and adaptive immune systems tribute to antimycobacterial innate immunity through secretion (Deretic, 2009, 2012). It is known that a variety of pathogen- of antibacterial effector molecules, cytokines, and chemokines, or danger-associated molecular patterns and pattern-recognition thus recruiting various immune cells to the site of infection (Jo receptor signaling are closely associated with autophagy activa- et al., 2007; Jo, 2010; Huynh et al., 2011; Kleinnijenhuis et al., tion (Xu et al., 2007; Delgado et al., 2008; Fabri et al., 2011a; 2011). In contrast, Mtb-mediated TLR2 signaling is associated Deretic, 2012). Therefore, it is not surprising that TLR signal- with generation of an environment favoring the survival of Mtb ing pathways triggered by engagement of mycobacterial antigens in macrophages (Yoshida et al., 2009). Together, TLR signaling in lead to activation of autophagy (Shin et al., 2010). The activa- mycobacterial infection acts as a double-edged sword regulating tion of autophagy influences the antigen-presenting capacity of a delicate balance in host innate and inflammatory responses to the immunodominant mycobacterial antigen Ag85B by antigen- determine disease outcome. presenting cells (Jagannath et al., 2009), as well as the production of antimicrobial proteins and pro-inflammatory cytokines HUMAN TLR POLYMORPHISM AND MYCOBACTERIAL (Yuk et al., 2009; Shin et al., 2010), thereby influencing vac- INFECTION cine efficacy and host immune defense during mycobacterial Human genetic polymorphisms of TLRs have a role in regulating infection. innate recognition of microbes and in determining susceptibil- Recent studies have uncovered the interplay of vitamin ity to mycobacterial infection. The relationship between TLR D-dependent antimicrobial responses and autophagy pathways polymorphisms, disease susceptibility, and innate immune activ- in the activation of host defense against mycobacterial infec- ities against mycobacteria has been described in several reviews tion (Yuk et al., 2009; Jo, 2010; Shin et al., 2010; Fabri (Texereau et al., 2005; Lykouras et al., 2008; Kleinnijenhuis et al., et al., 2011a). Activation of TLR signaling in human mono- 2011). Here we describe the recent data on genetic and functional cytes/macrophages has been shown to lead to the induction studies of TLRs in protection and pathogenesis of mycobacterial of the antimicrobial peptide cathelicidin, which is critically infection. It has been reported that TLR1/6-deficient genotypes involved in antimicrobial responses against Mtb (Liu et al., (typified by TLR1_T1805G and TLR6_C745T), after vaccination 2006, 2007; Yang et al., 2009). Physiological concentrations of with M. bovis BCG, are linked with the increased production 1,25D3 were found to be enough to induce the production of Th1-type T cell cytokines through regulation of monocyte of the human cathelicidin and autophagic flux, thereby acti- IL-10 production (Randhawa et al., 2011). Other recent stud- vating antimicrobial activities against Mtb and also inhibiting ies have reported that rs352139, an SNP located in the intron of HIV replication in cells co-infected with Mtb and HIV (Yuk TLR9 is associated with tuberculosis susceptibility in Indonesian et al., 2009; Campbell and Spector, 2012). Moreover, cathelicidin and Vietnamese populations (Kobayashi et al., 2012). It has also plays a dual role in vitamin D-induced autophagy activation in been reported that TLR8 polymorphisms are associated with pul- human monocytes/macrophages, acting both as a critical effec- monary tuberculosis susceptibility in males (Davila et al., 2008). tor of antimicrobial responses against Mtb and as a mediator Interestingly, TLR8 transcriptional levels are increased in patients of the autophagy pathway through enhancement of autophagic at the early phase of infection and TLR8 protein expression is flux and the induction of autophagy-related genes (Yuk et al., increased in macrophages after M. bovis BCG infection (Davila 2009; Campbell and Spector, 2012). Importantly, in human et al., 2008). macrophages cultured with vitamin D-sufficient sera, IFN-γ pro- Previously, it was shown that human TLR1 deficiency is linked duction by Th1 cells as well as stimulation of TLR2/1, turn on with impaired mycobacterial innate immune signaling and sus- antimicrobial activity through antimicrobial peptide expression, ceptibility to leprosy (Misch et al., 2008). Recent studies have autophagy activation, and phagosome-lysosome fusion (Fabri shown that TLR chaperones, PRAT4A, and PRAT4B are impor- et al., 2011b). These findings provide insights into how vitamin tant regulators in TLR1 trafficking to the cell surface and are D-dependent signaling triggers antimicrobial activity by activat- also regulated by IFN-γ (Hart and Tappiung, 2012). Furthermore, ing autophagy and regulating both innate and adaptive immune there is an inverse correlation between Euro-American lineage responses. of Mtb and extra-pulmonary dissemination, suggesting that a The impact of host autophagy on phagosome maturation and link between interaction between host and mycobacterial geno- Mtb killing gives rise to the idea that compounds that activate types and the clinical progression of tuberculosis (Caws et al., or modulate the autophagy pathway, could potentially enhance 2008). Future studies are warranted to define the exact relation- antimicrobial activities against Mtb infection (Gutierrez et al., ship between host and bacterial genotype and disease phenotype 2004; Singh et al., 2006; Fabri et al., 2011a; Kim et al., 2012; Lam using clinical isolates. et al., 2012; Zullo and Lee, 2012). Recent studies have shown that the prevalent anti-TB drugs isoniazid and pyrazinamide promote CROSS TALK BETWEEN TLR, AUTOPHAGY, AND VITAMIN D autophagy activation. This plays an important role in success- SIGNALING PATHWAYS ful antimicrobial responses during therapy against mycobacterial Several other innate immune pathways are closely linked with infection in vivo and in vitro (Kim et al., 2012). Lam et al. the TLR signaling pathway, thus cooperatively defining the innate also showed that the antiprotozoal drug nitazoxanide stimulates immune response which enables clearance of mycobacteria inside autophagy induction and mTORC1 inhibition, and inhibits Mtb

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proliferation in human monocytes and monocytic cells (Lam attractive possibility of developing therapeutics designed to aug- et al., 2012). ment autophagy as a means of restricting mycobacterial survival and combating infection. CONCLUDING REMARKS Developing vaccines and chemotherapeutic agents is the ACKNOWLEDGMENTS cornerstone of the successful management of tuberculosis. We are indebted to current and past members of our lab- Understanding the molecular mechanisms of speciﬁc interac- oratory for discussions and investigations that contributed tions of Mtb with its host should augment efforts in both these to this article. This work was supported by the Korea areas. Immune modulation as a strategy to combat mycobac- Science & Engineering Foundation through the Infection terial infection remains underexplored. This review brings to Signaling Network Research Center (R13-2007-020-01000-0) at light how mycobacterial modulins signaling through TLRs, con- Chungnam National University (Eun-Kyeong Jo), and by a tribute either to an effective host immune response or to grant (INT/Korea/P-10) from the Department of Science and immune evasion by the pathogen. Targeting those modulins that Technology, Government of India (Joyoti Basu) under the Indo- facilitate immune evasion, or exploiting those that facilitate a Korea Joint Program of Cooperation in Science and Technology. robust innate and adaptive immune response, could offer new We apologize to colleagues whose work and publications could avenues for controlling infection. The review also brings forth the not be referenced owing to space constraints.

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A doi: 10.1371/journal.ppat.1002620 interaction with TLR2 is required nal authors and source are credited and novel LPS-inducible C-type lectin is Shin,D.M.,Yuk,J.M.,Lee,H.M., for efficient innate immune subject to any copyright notices concern- a transcriptional target of NF-IL6 Lee,S.H.,Son,J.W.,Harding, responses to mycobacteria via ing any third-party graphics etc.

Frontiers in Cellular and Infection Microbiology www.frontiersin.org November 2012 | Volume 2 | Article 145 | 6