Trends in Microbiology
Volume 13, Issue 3, March 2005, Pages 119-127
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The worm has turned – microbial virulence modeled in Caenorhabditis elegans

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The nematode Caenorhabditis elegans is emerging as a facile and economical model host for the study of evolutionarily conserved mechanisms of microbial pathogenesis and innate immunity. A rapidly growing number of human and animal microbial pathogens have been shown to injure and kill nematodes. In many cases, microbial genes known to be important for full virulence in mammalian models have been shown to be similarly required for maximum pathogenicity in nematodes. C. elegans has been used in mutation-based screening systems to identify novel virulence-related microbial genes and immune-related host genes, many of which have been validated in mammalian models of disease. C. elegans-based pathogenesis systems hold the potential to simultaneously explore the molecular genetic determinants of both pathogen virulence and host defense.

Introduction

By September 1 2004, the genomes of 65 species of human and animal microbial pathogens had been completely sequenced, and at least 64 more were in the process of being determined. With this wealth of genetic information, there is an increasing need for simple and innovative ways to study microbial virulence strategies and assay the contribution of individual genes to pathogenesis. Recent efforts have demonstrated that many mammalian pathogenic bacteria and fungi can infect and cause disease in simple non-vertebrate hosts, such as the fruit fly Drosophila melanogaster, the roundworm Caenorhabditis elegans, and the plant Arabidopsis thaliana 1, 2, 3. Remarkably, many of the virulence mechanisms used by these microbes to cause disease in mammalian hosts have also been shown to be important for disease in the non-vertebrate surrogate hosts. Similarly, features of the germ-line-encoded host defense system, known as innate immunity, have also been evolutionarily conserved across phylogeny 4, 5, 6, 7, 8. Because both the host and pathogen are amenable to genetic analysis and high-throughput screening in each of these pathosystems, these models can be used both for the identification of microbial virulence factors and host immune-defense mechanisms. This review will focus on recent literature describing the use of C. elegans as a model host to study microbial pathogenesis. The reader is also referred to several other reviews that discuss the use of C. elegans pathogenesis models to study conserved features of the metazoan innate immune response 6, 7, 8, 9, 10, 11.

Section snippets

A variety of pathogens kill C. elegans

C. elegans is an anatomically simple, genetically tractable nematode that has been the subject of intense genetic study for nearly four decades and has been used to successfully model and investigate many biological processes (Box 1). As a terrestrial microbivore, C. elegans doubtlessly encounters and defends itself from many harmful environmental microorganisms in its natural habitat. But until recently, very few pathogenic interactions between C. elegans and microorganisms had been described

Infective pathogens accumulate in the C. elegans intestine

The antagonistic interactions between worms and P. aeruginosa remain a useful paradigm for C. elegans-based pathogenicity model systems. When P. aeruginosa strain PA14 is grown on minimal medium, it kills C. elegans relatively slowly over the course of several days. This killing, called ‘slow killing’ to differentiate it from toxin-mediated ‘fast killing’, correlates with the accumulation of live bacteria within the nematode digestive tract [13]. Large quantities of live bacteria also

Persistent infection of the C. elegans intestine

S. enterica, S. marcescens and E. faecalis not only accumulate in the C. elegans intestinal tract, but in contrast to P. aeruginosa and S. aureus, are also able to cause persistent infections 16, 21, 22, 23. For example, worms exposed to S. enterica for several hours and then transferred to lawns of E. coli die with similar kinetics to worms continuously exposed to the pathogen. Furthermore, S. enterica titers within the intestinal tract remain high several days after transfer to E. coli [21].

Colonization with biofilm formation on the worm cuticle

A different type of colonization has been observed to occur in the case of nematodes feeding on lawns of Y. pestis and Y. pseudotuberculosis. These bacteria form an obstructive matrix over the pharyngeal opening that accumulates over time and prevents normal feeding and nutrition [29]. Formation of this obstructive matrix is dependent on bacterial biofilm formation, because disruption of the hmsHFRS locus in both Y. pestis and Y. pseudotuberculosis, which is required for biofilm formation,

Toxin-mediated killing of C. elegans

An alternative mechanism that bacterial pathogens use to kill C. elegans involves the production of diffusible toxins. In these cases, nematode killing can be replicated by the toxin alone and does not require colonization of the intestinal tract with live bacteria. In some cases, these toxic natural products, notably the crystal toxins of Bacillus thuringiensis and the avermectin derivatives of Streptomyces avermitilis, have been developed into important commercial agents that are used in the

Microbial virulence factors important for worm killing

Microbial virulence factors can be separated into two broad categories. The first category includes those factors that have evolved to facilitate interaction of a given pathogen with its natural host(s). These highly specific products necessarily define the host range for a given pathogen. Factors of the second category are used in conserved virulence strategies by diverse pathogens to colonize, attack and evade their host [41]. Many of the genes encoding these common virulence factors are

Alteration of growth medium and conditions affects virulence

Another advantage of the C. elegans pathosystem is that the environment can be easily manipulated and its effect on virulence assessed. For example, changes in media composition can lead to dramatic changes in the virulence of a given pathogen. As discussed previously, P. aeruginosa strain PA14 grown in a rich medium kills worms after several hours because of the production of diffusible phenazine toxins. By contrast, the same strain of P. aeruginosa grown in minimal medium accumulates in the

Interactive genetic analysis between C. elegans mutants and pathogen mutants

Another experimental advantage of the C. elegans pathogenicity models is that genetic analysis can be readily carried out in both the pathogen and host, thereby permitting so-called interactive genetic analysis. This involves the identification of C. elegans mutants that suppress the attenuated phenotype of a pathogen mutant, or vice versa. The overall goal is to use genetic analysis to identify host function(s) that interact with a particular pathogen virulence factor(s). As an example, C.

Concluding remarks

It is now well established that the nematode C. elegans is a facile model host in which to study a variety of aspects of bacterial pathogenesis, although there are many outstanding questions that are the subject of continued research (Box 3). Irrespective of whether the molecular mechanisms underlying pathogenic processes have been evolutionarily conserved, a variety of C. elegans pathosystems have been used effectively to identify novel pathogen-encoded virulence factors that are relevant in

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