ReviewCaenorhabditis elegans as a host for the study of host–pathogen interactions
Introduction
An important question in the study of host–pathogen interactions is whether or not the underlying mechanisms of pathogenesis and host defense are highly conserved. Our laboratory and others have addressed this question by developing pathogenesis models that involve the infection of simple non-vertebrate hosts by human bacterial pathogens. For a given pathogen, if there is a large overlap between the virulence factors required to infect both the non-vertebrate and vertebrate hosts, then the basic mechanism of pathogenesis is most likely host-independent. Similarly, if a particular pathogen activates the same host-defense-related genes in both vertebrates and non-vertebrates, then the underlying mechanism of innate immunity is most likely highly conserved.
In this review, we shall focus on the use of Caenorhabditis elegans as the host for a variety of human pathogens. This organism's short 2–3-week life span and small (97 Mb), fully sequenced genome facilitate genetic and genomic analysis, offering an ideal compromise between complexity and tractability. Also, a wealth of data has demonstrated that a variety of developmental, neurological, cell biological and biochemical processes have been highly conserved between C. elegans and mammals.
Section snippets
C.elegans as a host for broad-host-range pathogens
Pseudomonas aeruginosa, a ubiquitous environmental organism and important opportunistic human pathogen, kills C. elegans by at least three distinct mechanisms, depending on the P. aeruginosa strain and the medium on which P. aeruginosa is grown 1., 2.. This illustrates a key aspect of the C. elegans model: the mode and extent of killing depends on a variety of genetic and environmental factors. Typically, C. elegans are propagated in the laboratory by feeding them Escherichia coli strain OP50
C. elegans as a host for specialized pathogens
Some pathogens that have co-evolved or have had a long-standing association with their hosts, such as Salmonella enterica, appear to utilize finely tuned host-specific strategies to establish a pathogenic relationship [7]. It has been proposed that, when Salmonella are present in the vertebrate intestinal lumen, they respond to a number of relevant environmental conditions by producing protein effectors that are translocated into host cells by a type III secretory system and that alter specific
Gram-positive human pathogens also kill C.elegans
Recent work from our laboratory shows that several Gram-positive human pathogens, including Streptococcus pneumoniae (pneumococcus), Staphylococcus aureus and Enterococcus faecalis, also kill adult C. elegans when the bacterial lawns are grown on brain–heart infusion medium, whereas other Gram-positives, including Streptococcus pyogenes (Group A streptococci) and Enterococcus faecium, do not kill. The failure of S. pyogenes and E. faecium to kill, however, must be evaluated in the context that
Microbacterium nematophilum, a natural C. elegans pathogen
A specific C. elegans pathogen, Microbacterium nematophilum, has been recently discovered. These bacteria adhere to the anal region of the nematodes and induce localized swelling of the underlying hypodermal tissue. Although the C. elegans–M. nematophilum interaction is non-lethal for the worm, it has been suggested to be parasitic, owing to the morphological changes in and lack of obvious benefits for the host [12].
Pathogen virulence factors involved in C. elegans killing
Both forward and reverse genetic analyses have been used to identify bacterial virulence factors that are required for C. elegans killing as well as mammalian pathogenesis, thereby validating the use of C. elegans as a model host. Interestingly, the bacterial virulence factors identified in studies of this type will most likely depend on the environmental conditions used for screening for mutant phenotypes. For example, in the case of P. aeruginosa PA14, screening of a random transposon
Reverse genetic analysis of the C. elegans innate immune response
Essentially nothing is known about the C. elegans innate immune response to bacterial pathogens. Although C. elegans and Drosophila melanogaster have been placed in sister phyla, C. elegans does not appear to have an intact Toll signaling pathway, a central feature of the insect and mammalian innate immune responses. In insects and mammals, a set of Toll-like receptors appears to be involved in the recognition of pathogen-associated molecular patterns (PAMPS), defined as components of
C. elegans defense mechanisms against bacterial toxins
In addition to Toll and PCD pathway components, several other C. elegans genes have been tested for their roles in pathogen resistance. For example, certain C. elegans P-glycoprotein (pgp) mutants that have defective efflux pumps are hypersusceptible to P. aeruginosa P14-mediated fast killing, but not slow killing. This was shown to be due to the synthesis by PA14 of pyocyanin, a tricyclic secondary metabolite that reacts with oxygen to form active oxygen species, including superoxide and
C. elegans defense mechanisms against nematode-specific pathogens
In the case of the nematode-specific pathogen M. nematophilum, about 200 C. elegans mutants have been examined for enhanced susceptibility or resistance [12]. Certain mutants with altered surface antigenicity (srf-2, srf-3 and srf-5) 24., 25. were found to be resistant to infection by M. nematophilum. Resistance in this case appears to be due to a change in the surface properties of the cuticle that blocks adherence of the bacteria. Interestingly, the three mutants that are more resistant to M.
Forward genetic analysis to identify C. elegans defense mechanisms against bacterial infections
As described above, the power of the C. elegans genetic system can be readily exploited to identify mutants that are either more susceptible or more resistant to bacterial killing. Hopefully, some of these mutants will correspond to components of a general C. elegans innate immune response. For example, by using P. aeruginosa as the pathogen, several C. elegans mutants (called enhanced susceptibility to pathogens [esp] mutants) that exhibit hypersusceptibility to pathogen-mediated killing have
Conclusions
C. elegans has proven to be an efficient host model for both broad-host-range and specialized human pathogens. As validation of the relevance of the C. elegans model, a variety of studies have shown that there is a significant amount of overlap between the pathogen genes involved in C. elegans killing and mammalian pathogenesis. Also, several genes involved in host defense responses have been identified. Further studies using the power of C. elegans genetic and genomic analyses are expected to
Update
Recent work has demonstrated that pertussis toxin expression in transgenic C. elegans produces a phenotype that suggests that the toxin target is conserved between mammals and nematodes [27••]. Moreover, it has been reported that hydrogen cyanide is the primary toxic component that mediates the paralytic killing of C. elegans caused by P. aeruginosa PAO1 [4]. Hydrogen cyanide exerts its effect on C. elegans through EGL-9 or on a pathway that includes it. Intriguingly, EGL-9 was recently
Acknowledgements
We thank Jonathan Ewbank and Jeffrey Jeddeloh for helpful comments on the manuscript and for communicating results prior to publication.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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