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Genetic, Molecular and Physiological Basis of Variation in Gut Immunocompetence

ABSTRACT: Gut immunocompetence involves immune, stress, and regenerative processes. To investigate the determinants underlying inter-individual variation in gut immunocompetence, we perform enteric infection of 140 Drosophila lines with the entomopathogenic bacterium Pseudomonas entomophila and observe extensive variation in survival. Using genome-wide association analysis, we identify several novel immune modulators. Transcriptional profiling further shows that the intestinal molecular states of resistant and susceptible lines differ, already before infection, with one transcriptional module involving genes linked to reactive oxygen species (ROS) metabolism contributing to this difference. This genetic and molecular variation is physiologically manifested in lower ROS activity, lower susceptibility to ROS-inducing agent, faster pathogen clearance and higher stem cell activity in resistant versus susceptible lines. This study provides novel insights into the determinants underlying population-level variability in gut immunocompetence, revealing how relatively minor, but systematic genetic and transcriptional variation can mediate overt physiological differences that determine enteric infection susceptibility.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE59411 | GEO | 2015/06/02

SECONDARY ACCESSION(S): PRJNA255258

REPOSITORIES: GEO

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Project description:Resistance to enteric pathogens is a complex trait at the crossroads of multiple biological processes. We have previously shown in the Drosophila Genetic Reference Panel (DGRP) that resistance to infection is highly heritable, but our understanding of how the effects of genetic variants are channeled through distinct molecular layers is still limited. To address this, we employed a systems genetics approach on the gut transcriptomes from 38 control and orally-infected DGRP lines, identifying a large number of condition-specific expression quantitative trait loci (cis-eQTLs). By assessing the allelic imbalance in the transcriptomes of 19 F1 hybrid lines from a large round-robin design, we could independently attribute a robust cis-regulatory effect to only 10% of the detected cis-eQTLs. These results therefore suggest that many context-dependent eQTLs that are assumed to act in cis, may act in trans instead. Further comparison of the transcriptomes of resistant and susceptible DGRP lines revealed Nutcracker (ntc) as the only differentially expressed gene between resistance classes. Interestingly, we found that ntc is linked to infection-specific eQTLs that not only correlate with its expression level, but also to enteric infection susceptibility. This is consistent with our findings that ntc expression is induced upon infection, whereas loss of ntc confers an overall greater susceptibility to infection, including lower innate immune activation as well as impaired infection-induced stem cell activity. Further mechanistic analysis revealed one ntc eQTL that significantly decreases the binding affinity for the repressor Broad, resulting into an allele-specific ntc expression increase. Our collective findings therefore point to a large number of infection-specific cis and trans-acting eQTLs in the DGRP, including one common non-coding variant that lowers enteric infection susceptibility by modulating ntc gene regulation through altered Broad repressor binding.

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Genetic, Molecular and Physiological Basis of Variation in Gut Immunocompetence

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