Caenorhabditis elegans for the study of host-pathogen interactions

The nematode worm Caenorhabditis elegans, for which the complete genome sequence is available, has several other advantages as an experimental system, and has already been widely used as a model for the study of vertebrate biology. Recent investigations have revealed that C. elegans could also be an extremely useful model system in the study of bacterial pathogenesis and have reinforced the notion that common virulence and host defence mechanisms exist.     

The nematode Caenorhabditis elegans as a model for the study of host-pathogen interactions

For certain pathogens capable of infecting a broad range of organisms, there exist universal virulence factors, necessary for full pathogenicity regardless of the host. This has been most clearly demonstrated by Ausubel and colleagues for the human opportunistic pathogen Pseudomonas aeruginosa. As a consequence, one can use non-mammalian model systems, including the nematode worm Caenorhabditis elegans, to assay for such virulence factors. A significant number of pathogens of C. elegans, that provoke a range of diseases, are now known, including the opportunistic human pathogen Serratia marcescens. After explaining the practical advantages associated with the use of C. elegans, and briefly reviewing previous studies, the results of a screen for S. marcescens virulence factors will be presented.     

Tackling both sides of the host-pathogen equation with Caenorhabditis elegans

If one is interested in dissecting the complex interactions that exist between host and pathogen, the nematode worm Caenorhabditis elegans is perhaps not the first model host that comes to mind. In this review I will introduce 'the worm' and try to show how it is, in fact, well suited to the identification of universal virulence factors and holds great promise for the study of conserved mechanisms of innate immunity.     

Caenorhabditis elegans is a model host for Listeria monocytogenes

Here we report that Caenorhabditis elegans nematodes fed Listeria monocytogenes die over the course of several days, as a consequence of an accumulation of bacteria in the worm intestine. Mutant strains previously shown to be important for virulence in mammalian models were also found to be attenuated in their virulence in C. elegans. However, ActA, which is required for actin-based intracellular motility, appears to be dispensable during infection of C. elegans, indicating that L. monocytogenes remains extracellular in C. elegans.     

Caenorhabditis elegans is a model host for Salmonella typhimurium

The idea of using simple, genetically tractable host organisms to study the virulence mechanisms of pathogens dates back at least to the work of Darmon and Depraitère [1]. They proposed using the predatory amoeba Dictyostelium discoideum as a model host, an approach that has proved to be valid in the case of the intracellular pathogen Legionella pneumophila [2]. Research from the Ausubel laboratory has clearly established the nematode Caenorhabditis elegans as an attractive model host for the study of Pseudomonas aeruginosa pathogenesis [3]. P. aeruginosa is a bacterium that is capable of infecting plants, insects and mammals. Other pathogens with a similarly broad host range have also been shown to infect C. elegans [3,4]. Nevertheless, the need to determine the universality of C. elegans as a model host, especially with regards pathogens that have a naturally restricted host specificity, has rightly been expressed [5]. We report here that the enterobacterium Salmonella typhimurium, generally considered to be a highly adapted pathogen with a narrow range of target hosts [6], is capable of infecting and killing C. elegans. Furthermore, mutant strains that exhibit a reduced virulence in mammals were also attenuated for their virulence in C. elegans, showing that the nematode may constitute a useful model system for the study of this important human pathogen.     

Caenorhabditis elegans-based screen identifies Salmonella virulence factors required for conserved host-pathogen interactions

A Caenorhabditis elegans-Salmonella enterica host-pathogen model was used to identify both novel and previously known S. enterica virulence factors (HilA, HilD, InvH, SptP, RhuM, Spi4-F, PipA, VsdA, RepC, Sb25, RfaL, GmhA, LeuO, CstA, and RecC), including several related to the type III secretion system (TTSS) encoded in Salmonella pathogenicity island 1 (SPI-1). Mutants corresponding to presumptive novel virulence-related genes exhibited diminished ability to invade epithelial cells and/or to induce polymorphonuclear leukocyte migration in a tissue culture model of mammalian enteropathogenesis. When expressed in C. elegans intestinal cells, the S. enterica TTSS-exported effector protein SptP inhibited a conserved p38 MAPK signaling pathway and suppressed the diminished pathogenicity phenotype of an S. enterica sptP mutant. These results show that C. elegans is an attractive model to study the interaction between Salmonella effector proteins and components of the innate immune response, in part because there is a remarkable overlap between Salmonella virulence factors required for human and nematode pathogenesis.     

Caenorhabditis elegans as a model for lysosomal storage disorders

The nematode Caenorhabditis elegans is the simplest animal model available to study human disease. In this review, the worm homologues for the 58 human genes involved in lysosomal storage disorders and for 105 human genes associated with lysosomal function have been compiled. Most human genes had at least one worm homologue. In addition, the phenotypes of 147 mutants, in which these genes have been disrupted or knocked down, have been summarized and discussed. The phenotypic spectrum of worm models of lysosomal storage disorders varies from lethality to none obvious, with a large variety of intermediate phenotypes. The genetic power of C. elegans provides a means to identify genes involved in specific processes with relative ease. The overview of potential lysosomal phenotypes presented here might be used as a starting point for the phenotypic characterization of newly developed knock-out models or for the design of genetic screens selecting for loss or gain of suitable knock-out model phenotypes. Screens for genes involved in lysosomal biogenesis and function have been performed successfully resulting in the cup and glo mutants, but screens involving subtle phenotypes are likely to be difficult.     

The nematode Caenorhabditis elegans as a model to study the roles of proteoglycans

The nematode Caenorhabditis elegans is a powerful animal model for exploring the genetic basis of metazoan development. Recent genetic and biochemical studies have revealed that the molecular machinery of glycosaminoglycan (GAG) biosynthesis and modification is highly conserved between C. elegans and mammals. In addition, genetic studies have implicated GAGs in vulval morphogenesis and zygotic cytokinesis. The extensive knowledge of C. elegans biology, including its elucidated cell lineage, together with the completed and well annotated DNA sequence and availability of reverse genetic tools, provide a platform for studying the functions of proteoglycans and their GAG modification. Published in 2003.     

Glia-neuron interactions in the nervous system of Caenorhabditis elegans

A century and a half after first being described, glia are beginning to reveal their intricate and important roles in nervous system development and function. Recent studies in the nematode Caenorhabditis elegans suggest that this invertebrate will provide important insight into these roles. Studies of C. elegans have revealed a connection between glial ensheathment of neurons and tubulogenesis, have uncovered glial roles in neurite growth, navigation, and function, and have demonstrated roles for glia and glia-like cells in synapse formation and function. Given the conservation of basic anatomical, functional and molecular features of the nervous systems between C. elegans and vertebrates, these recent advances are likely to be informative in describing nervous system assembly and function in all organisms possessing a nervous system.     

Beyond host-pathogen interactions: microbial defense strategy in the host environment

Many extracellular pathogenic bacteria colonize human or animal bodies through evasion of the host immune system, a process called host-pathogen interaction. What happens when other intruders try to invade the same host and try to establish themselves in the same niche is largely unknown. In one well-studied case, Pseudomonas aeruginosa is known to secrete the protein azurin as a weapon against such invaders as cancers, parasites and viruses. The production of such weapons by pathogenic bacteria could provide important insights into how a pathogen responds in the post-colonization state to impede other intruders for its own survival. Moreover, these molecules might find use in the pharmaceutical industry as next-generation therapeutics.     

Characterization of mediators of microbial virulence and innate immunity using the Caenorhabditis elegans host-pathogen model

The soil-borne nematode, Caenorhabditis elegans, is emerging as a versatile model in which to study host-pathogen interactions. The worm model has shown to be particularly effective in elucidating both microbial and animal genes involved in toxin-mediated killing. In addition, recent work on worm infection by a variety of bacterial pathogens has shown that a number of virulence regulatory genes mediate worm susceptibility. Many of these regulatory genes, including the PhoP/Q two-component regulators in Salmonella and LasR in Pseudomonas aeruginosa, have also been implicated in mammalian models suggesting that findings in the worm model will be relevant to other systems. In keeping with this concept, experiments aimed at identifying host innate immunity genes have also implicated pathways that have been suggested to play a role in plants and animals, such as the p38 MAP kinase pathway. Despite rapid forward progress using this model, much work remains to be done including the design of more sensitive methods to find effector molecules and further characterization of the exact interaction between invading pathogens and C. elegans' cellular components.     

Virulence of Leucobacter chromiireducens subsp. solipictus to Caenorhabditis elegans: characterization of a novel host-pathogen interaction

We describe the pathogenic interaction between a newly described gram-positive bacterium, Leucobacter chromiireducens subsp. solipictus strain TAN 31504, and the nematode Caenorhabditis elegans. TAN 31504 pathogenesis on C. elegans is exerted primarily through infection of the adult nematode uterus. TAN 31504 enters the uterus through the external vulval opening, and the ensuing uterine infection is strongly correlated with a significant reduction in host life span. Young worms can feed and develop on TAN 31504, but not preferably over the standard food source. C. elegans worms reared on TAN 31504 as the sole food source develop into thin adults with little intestinal fat stores, produce few progeny, and subsequently cannot persist on the pathogenic food source. Within 12 h of exposure, adult worms challenged with TAN 31504 alter the expression of a number of C. elegans innate immunity-related genes, including nlp-29, which encodes a neuropeptide-like protein. C. elegans worms exposed briefly to TAN 31504 develop lethal uterine infections analogous to worms exposed continuously to pathogen, suggesting that mere contact with the pathogen is sufficient for the host to become infected. TAN 31504 produces a robust biofilm, and this behavior is speculated to play a role in the virulence exerted on the nematode host. The interaction between TAN 31504 and C. elegans provides a convenient opportunity to study bacterial virulence on nematode tissues other than the intestine and may allow for the discovery of host innate immunity elicited specifically in response to vulva-uterus infection.     

Caenorhabditis elegans as a model system to study aging of learning and memory

The nematode Caenorhabditis elegans is an excellent model organism to study biological processes relevant to a wide variety of human and rodent disease systems. Previous studies have suggested that mutants of the insulin/insulin-like growth factor-1 pathway show life extension and increased stress resistance in various species, including C. elegans, the fruit fly, and the mouse. It has recently been shown that the life-extending mutants, including the age-1 phosphatidylinositol- 3 OH kinase mutants and the daf-2 insulin-like receptor mutants, display improvement in a type of associative learning behavior called thermotaxis learning behavior. The age-1 mutant shows a dramatic threefold extension of the health-span that ensures thermotaxis learning behavior, suggesting strong neuroprotective actions during aging. The age-1 and daf-2 mutants show resistance to multiple forms of stress and upregulates the genes involved in reactive oxygen species scavenging, heat shock, and P450 drug-detoxification. The life-extending mutants may confer resistance to various stress and diseases in neurons. Therefore, C. elegans provides an emerging system for the prevention of age-related deficits in the nervous system and in learning behaviors. This article discusses the aging of learning and memory and the neuroprotection effects of life-extending mutants on learning behaviors.     

Neuronal mechanisms of Caenorhabditis elegans and pathogenic bacteria interactions

Individuals interact with environment through different neuronal functions, such as olfaction and mechanosensation; experience shapes these physiological functions. It is not well understood how an individual senses and processes multiple cues of natural stimuli in the environment and how experience modulates these physiological mechanisms. Recent molecular genetics and behavioral studies on the interactions of the genetic model organism Caenorhabditis elegans with pathogenic bacteria have provided insights on the molecular and cellular mechanisms underlying these regulatory processes.     

Mos as a tool for genome-wide insertional mutagenesis in Caenorhabditis elegans: results of a pilot study

The sequence of the Caenorhabditis elegans genome contains approximately 19 000 genes. Available mutants currently exist for <20% of these genes. The existence of a Mos-based inducible transposon system in C.elegans could theoretically serve as a tool to saturate the genome with insertions. We report here the results of a pilot study aimed at assaying this strategy. We generated 914 independent random Mos insertions and determined their location by inverse PCR. The distribution of the insertions throughout the genome does not reveal any gross distortion, with the exception of a major hotspot on chromosome I (rDNA locus). Transposons are evenly distributed between the genic and intergenic regions. Within genes, transposons insert preferentially into the introns. We derived the consensus target site for Mos in C.elegans (ATATAT), which is common to Tc1, another mariner element. Finally, we assayed the mutagenic properties of insertions located in exons by comparing the phenotype of homozygous strains to that of known mutations or RNAi of the same gene. This pilot experiment shows that a Mos-based approach is a viable strategy that can contribute to the constitution of genome-wide collections of identified C.elegans mutants.     

Sex and polymorphism as strategies in host-pathogen interactions

Sexual reproduction in a polymorphic population generates ever novel recombinations. It is shown that this variety is essential in preventing pathogens from adaptively breaking through immunological host resistance. The theory explains the extensive polymorphism of wild-type populations and catastrophic diseases in genetically homogeneous cultivars. It offers a new model of the selective forces that maintain sex. It interprets self-incompatibility in angiosperms as a mechanism that maintains polymorphism. An analogous mechanism involving sperm selection based on histocompatibility haplotype is postulated for mammalian fertilization. Mate selection involving odor clues is conjectured for eusocial insects. Population regulation of asexual species through pathogens also involves polymorphism. The proposed theory of polymorphism overcomes difficulties present in the balanced and neutral selection theory of mathematical genetics.     

Caenorhabditis elegans as a model for parasitic nematodes: a focus on the cuticle

The phylum Nematoda consists of over half a million species of worms that inhabit astoundingly diverse environments. Nematodes can live as obligatory parasites of plants and animals, or alternate a parasitic with a free-living life style. The fact that the vast majority of species are strictly free living often surprises parasitology students, for obviously the highest research priorities in this field have involved parasites of medical, veterinary and agricultural importance. Here Samuel Politz and Mario Philipp contend that some basic questions concerning the biology of the parasite cuticle can be investigated more easily and in greater depth in the free-living nematode Caenorhabditis elegans than in the parasites themselves.