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. 2007;8(9):R194.
doi: 10.1186/gb-2007-8-9-r194.

Genome-wide investigation reveals pathogen-specific and shared signatures in the response of Caenorhabditis elegans to infection

Daniel Wong  1 , Daphne Bazopoulou, Nathalie Pujol, Nektarios Tavernarakis, Jonathan J Ewbank
Affiliations

Genome-wide investigation reveals pathogen-specific and shared signatures in the response of Caenorhabditis elegans to infection

Daniel Wong et al. Genome Biol. 2007.

Abstract

Background: There are striking similarities between the innate immune systems of invertebrates and vertebrates. Caenorhabditis elegans is increasingly used as a model for the study of innate immunity. Evidence is accumulating that C. elegans mounts distinct responses to different pathogens, but the true extent of this specificity is unclear. Here, we employ direct comparative genomic analyses to explore the nature of the host immune response.

Results: Using whole-genome microarrays representing 20,334 genes, we analyzed the transcriptional response of C. elegans to four bacterial pathogens. Different bacteria provoke pathogen-specific signatures within the host, involving differential regulation of 3.5-5% of all genes. These include genes that encode potential pathogen-recognition and antimicrobial proteins. Additionally, variance analysis revealed a robust signature shared by the pathogens, involving 22 genes associated with proteolysis, cell death and stress responses. The expression of these genes, including those that mediate necrosis, is similarly altered following infection with three bacterial pathogens. We show that necrosis aggravates pathogenesis and accelerates the death of the host.

Conclusion: Our results suggest that in C. elegans, different infections trigger both specific responses and responses shared by several pathogens, involving immune defense genes. The response shared by pathogens involves necrotic cell death, which has been associated with infection in humans. Our results are the first indication that necrosis is important for disease susceptibility in C. elegans. This opens the way for detailed study of the means by which certain bacteria exploit conserved elements of host cell-death machinery to increase their effective virulence.

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Figures

Figure 1
Figure 1
Comparison of host gene expression profiles following infection with different pathogens. Expression levels are indicated by a color scale and represent normalized differences between infected and control animals. Grey denotes genes not considered to be differentially regulated under that condition. The numbers on the vertical axis correspond to differentially regulated genes. Each column shows the expression levels of individual genes (represented as rows) following infection by the pathogens as indicated on the horizontal axis (S. m, S. marcescens; E. f, E. faecalis; E. c, E. carotovora; P. l, P. luminescens). (a) Genes differentially regulated in an infection with P. luminescens and their comparative expression levels with other pathogens. (b) Genes defining a pathogen-specific signature specifically up-regulated with P. luminescens infection. (c) Groupings, as indicated by the horizontal bars, formed after clustering using non-redundant sets of genes that were up- and down-regulated by at least two pathogens (trees not shown). (d) Genes commonly up-regulated following E. carotovora, E. faecalis and P. luminescens infections.
Figure 2
Figure 2
Gene classes within gene expression profiles identified using EASE. Significantly enriched gene classes (p value < 0.05) with genes that were differentially regulated following infection with the four pathogens (S. m, S. marcescens; E. f, E. faecalis; E. c, E. carotovora; P. l, P. luminescens). Expression profiles were either (a) similar, or (b) different across pathogens. Numbers shown indicate the number of genes significant in that gene class, whilst relevant biological themes are indicated with lines in different colors.
Figure 3
Figure 3
qRT-PCR analyses. (a) Expression levels of common response genes representing two gene families were measured and data reported as mean difference between infected and control animals following infection with the four pathogens (S. m, S. marcescens; E. f, E. faecalis; E. c, E. carotovora; P. l, P. luminescens). (b) The expression levels of asp-3, asp-6 and clec-63 were followed over a period of five days in C. elegans infected with S. marcescens; data reported as mean difference between infected and control animals. Bars represent standard errors (at least two independent measurements). (c) The antimicrobial gene nlp-29 responds specifically to fungal infection. The expression levels of nlp-29 were measured following infection with the fungal pathogen (D. c, D. coniospora) and the four bacterial pathogens. Data are reported as mean difference between infected and control animals. Bars represent standard errors (three independent measurements).
Figure 4
Figure 4
Expression domains of common response genes and symptoms associated with infection. pF44A2.3::GFP expression in the (a) ventral nerve-cord, (b) hypodermis, (c-d) P12.pa pre-anal cells, (e-f) glial amphid socket cells, (g-h) excretory duct cell and (i) vulE or uv1 cells. Red fluorescence comes from the pcol-12::dsRED co-injection marker. In areas where both GFP and dsRED are expressed, yellow is observed. (j,k) Vacuoles (arrows) can be observed within intestinal cells of P. luminescens-infected adults (j), in which there is detectable expression of asp-4::GFP (k). Similar results were obtained with infected adults expressing asp-3::GFP. In contrast, no GFP expression or vacuolization was seen in the intestines of non-infected worms.
Figure 5
Figure 5
Suppression of necrosis increases resistance of worms to infection. Both vha-12(n2915) and unc-32(e189) are associated with a defect in vacuolar H+-ATPase activity and, consequently, reduced necrosis. Following infection with (a) E. carotovora and E. carotovora (b) E. carotovora, the differences between wild-type N2 and vha-12(n2915) or unc-32(e189) survival are highly significant (log-rank test, p value < 0.0001). Data shown are representative of three independent experiments. (c,d) Bacterial load in the intestines of wild-type and mutant C. elegans (indicated on the horizontal axes), after 24 h exposure to E. carotovora (c) and P. luminescens (d). The number of colony-forming units (CFU) per worm was measured and bars represent the standard errors from two independent experiments. (e) Life-span assays for the mutants vha-12(n2915) and unc-32(e189) and wild-type N2 on non-pathogenic OP50 E. coli. Differences between the three strains are not significant (log-rank test, p value > 0.05).
Figure 6
Figure 6
Modeling the molecular basis underlying an intestine-localized, pathogen-shared response to infection in C. elegans. Three major components make up the model; the common response genes identified directly in this study, genes associated with common response genes on the basis of shared DNA motifs, and interactors of the common response genes, either genetic (Wormbase) or physical (core or scaffold; InteractomeDB). Unambiguous evidence for expression in the intestine exists for all indicated genes. The relevant biological functions are shown in different colors.
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