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Studying Host-Pathogen Interactions and Innate Immunity in Caenorhabditis Elegans

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Studying Host-Pathogen Interactions and Innate Immunity in Caenorhabditis Elegans Studying host-pathogen interactions and innate immunity in Caenorhabditis elegans The MIT Faculty has made this article openly available. Please share how this access benefits you. Your story matters. Citation Kim, D. “Studying Host-pathogen Interactions and Innate Immunity in Caenorhabditis Elegans.” Disease Models and Mechanisms 1.4-5 (2008): 205–208. Copyright © 2008 Published by The Company of Biologists Ltd As Published http://dx.doi.org/10.1242/dmm.000265 Publisher Company of Biologists Version Final published version Citable link http://hdl.handle.net/1721.1/76794 Terms of Use Creative Commons Attribution-Noncommercial-Share Alike 3.0 Detailed Terms http://creativecommons.org/licenses/by-nc-sa/3.0/ Disease Models & Mechanisms 1, 205-208 (2008) doi:10.1242/dmm.000265 PRIMER Studying host-pathogen interactions and innate immunity in Caenorhabditis elegans Dennis Kim1 The genetic analysis of mechanisms of pathogen resistance in the nematode be able to infect an evolutionarily diverse range of hosts (Rahme et al., 1995). P. aerug- Caenorhabditis elegans has revealed a role for evolutionarily conserved signaling inosa infection leads to death of the worm pathways that are required for innate immunity in a wide range of organisms, from within 2-3 days; the C. elegans killing worms to mammals. C. elegans represents one of the more simple host organisms process is dependent on a number of bac- in which mechanisms of host defense can be dissected, and the use of C. elegans terial virulence factors that are also required presents the researcher with a wide array of genetic and genomic tools to probe for pathogenesis in mammalian hosts (Tan the host-pathogen interface. The study of host defense mechanisms in C. elegans et al., 1999a; Tan et al., 1999b). Under spe- continues to provide an ancient evolutionary perspective on innate immunity, cific experimental conditions, P. aeruginosa can also kill C. elegans through the secre- which may generate insights into the conserved processes in phylogenetically tion of toxins (Darby et al., 1999; Mahajan- diverse host organisms, including humans. Miklos et al., 1999). Of note, even Salmo- nella species, which unlike P. aeruginosa are DMM generally thought to have a narrow, highly C. elegans AS A HOST ORGANISM FOR THE immune signaling and protective effector specific host tropism, have been shown to STUDY OF IMMUNITY: WHY AND HOW? responses. What these approaches have in infect and kill C. elegans (Aballay et al., 2000; Innate immunity serves as the first line of common is the analysis of a genetically Labrousse et al., 2000). defense against infection, with roles in the tractable host that facilitates the identifica- The initial bias in the development of initial recognition of pathogens, the devel- tion and characterization of evolutionarily experimental host-pathogen systems opment of a neutralizing response, and conserved mechanisms of host defense. involving bacterial or fungal infection of C. mobilization of the adaptive immune Here, I discuss the use of the nematode elegans has been to use microbial response (Akira et al., 2006). The innate Caenorhabditis elegans as a genetically pathogens of humans, in part because of immune system is crucial for normal host tractable host organism in which to dissect interest in using the C. elegans host to dis- defense, but dysregulation of the innate mechanisms of innate immunity. Following sect virulence mechanisms in the human immune system is implicated in a number the sequencing of the C. elegans genome pathogens. In addition, at least two infec- of pathological states, such as in chronic (Sternberg, 2001), there has been a dramatic tions that appear to occur naturally in C. inflammatory diseases. Studies of the reg- increase in the development of technologies elegans have been characterized in detail. ulation of antimicrobial peptides in the that have facilitated the study of immunity First, Microbacterium nematophilum Drosophila and mouse immune responses in C. elegans. adheres to the cuticle of C. elegans and Disease Models & Mechanisms to lipopolysaccharide revealed the func- The standard propagation of C. elegans induces a protective, local anal swelling tional conservation of Toll signaling in in the laboratory involves growing the response that results in compromised defe- immunity between insects and mammals nematodes on lawns of attenuated cation function (Hodgkin et al., 2000). Sec- (Lemaitre et al., 1996; Poltorak et al., 1998). Escherichia coli strains that allow the worms ond, Drechmeria coniospora is a member The convergence of these genetic analyses to survive for 3 weeks. Interest in the devel- of the agriculturally important nematoph- in evolutionarily diverse hosts suggested opment of alternative hosts to study mech- gous fungi that capture C. elegans and kill that the study of simple invertebrate systems anisms of bacterial pathogenesis has led a the worms through conidia that penetrate could shed light on the ancient evolution- number of groups to develop experimental the outer cuticle and epidermal layers of ary origins and conserved signaling mech- host-pathogen systems in which the C. ele- C. elegans (Couillault et al., 2004). The dif- anisms of mammalian innate immunity gans host feeds on pathogenic bacteria or ferent modes of infection of C. elegans are (Hoffmann et al., 1999). fungi (Couillault and Ewbank, 2002; Couil- depicted in Figure 1. Little is known about In recent years, studies involving a diver- lault et al., 2004; Darby et al., 1999; Garsin the natural ecology and microbial flora that sity of simple organisms, including et al., 2001; Mahajan-Miklos et al., 1999; C. elegans encounters in the wild; although, zebrafish, fruitflies, mosquitoes, worms and Mylonakis et al., 2002; Tan et al., 1999a). as a soil nematode, C. elegans undoubtedly Dictyostelium have addressed basic ques- A number of initial studies have used encounters innumerable microorganisms, tions at the host-pathogen interface, includ- the human opportunistic pathogen some of which are pathogenic. Such infor- ing aspects of pathogen recognition, Pseudomonas aeruginosa, which appears to mation will help to illuminate studies of C. elegans immunity and provide insights into 1Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA the evolution of specific host defense (e-mail: [email protected]) mechanisms in C. elegans. Disease Models & Mechanisms 205 PRIMER Innate immunity in C. elegans showed increased mortality following Sal- monella infection (Tenor and Aballay, 2008). Interestingly, no orthologs of the crucial downstream TLR signaling component MyD88, or the downstream transcription A factor NF-kB, are predicted to be encoded C by the C. elegans genome (Pujol et al., 2001). B The other gene encoding a TIR domain protein in C. elegans is tir-1, which encodes an ortholog of the human TIR domain pro- Intestine Tail tein SARM, also referred to as MyD88-5 E is piderm (Mink et al., 2001). SARM is one of five Fig. 1. Different modes of infection of C. elegans elicit immune responses. Three distinct modes of members of the TIR adaptor protein fam- infection of C. elegans have been described that elicit conserved innate immune signaling pathways. ily that includes MyD88, MAL, TRIF and (A) Intestinal infection with a wide range of pathogens involves proliferation of bacteria in the intestinal TRAM (O’Neill and Bowie, 2007). TIR-1 lumen. (B) The nematophagous fungus Drechmeria initiates infection by attachment to the cuticle with functions upstream of the ASK1-depen- subsequent penetration of the epidermis. (C) The attachment of M. nematophilum to the tail region of dent PMK-1 p38 MAPK pathway in C. elegans and subsequent rectal invasion induces a protective swelling response at the site of infection. pathogen defense (Liberati et al., 2004). In addition, TIR-1 is required for immunity to intestinal pathogens, as well as the epider- CONSERVED PATHWAYS OF IMMUNE aeruginosa, but also other intestinal mal expression of the antifungal peptide SIGNALING IN C. elegans pathogens including Salmonella, Gram- NLP-29 in response to the nematophagous DMM Studies of immunity in C. elegans have positive pathogens such as Enterococcus fungus Drechmeria coniospora (Couillault et focused on three principal approaches: (1) faecalis and Staphylococcus aureus, and al., 2004). A role for TIR-1 in neuronal forward genetic screening for mutants with pathogenic fungi such as Cryptococcus neo- development has also been demonstrated in altered pathogen susceptibility, (2) reverse formans (Aballay et al., 2003; Kim et al., AWC chemosensory neurons, where TIR- genetic approaches assaying the role of con- 2002; Mylonakis et al., 2002; Sifri et al., 1 was found to function in ASK1-dependent served genes that are known to function in 2003). In addition, based on the analysis of activation of a MAPK that is distinct from innate immunity in other organisms, and (3) C. elegans resistance to E. coli which have PMK-1 (Chuang and Bargmann, 2005). analysis of gene expression that is either been engineered to express the Bt toxin Subsequently, studies of the role of induced by pathogenic infection, or under (Huffman et al., 2004), a toxin of important SARM in mammals have provided con- the regulation of immune signaling path- agricultural interest expressed by Bacillus flicting results regarding its role in innate ways. thurigiensis, the p38 MAPK pathway has immunity. Overexpression of SARM A genetic screen for mutants with been implicated in defense against
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