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 state differs between resistant and susceptible lines, 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.
Highlights
Gut immunocompetence involves immune, stress and regenerative processes
These results suggest that the Drosophila Genetic Reference Panel (DGRP) phenotypes observed for P. entomophila infection may reflect a more general pattern in that they may be due to a common, likely bacterium-independent genetic and molecular mechanism that mediates oral infection susceptibility
The aim of our study was to go beyond these classical analyses to uncover first of all the extent of inter-individual variation in gut immunocompetence and in a subsequent step the underlying genetic and molecular determinants
Summary
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. The use of inbred fly lines allows assessment of the impact of infection on distinct, but constant genetic backgrounds to tease out the effect of the genotype from environmental effects[18,19,20,21,22,23,24] This ability has been previously exploited to examine naturally occurring variation in pathogen susceptibility at a systemic level[22,23,24], albeit to our knowledge not yet in the gut. We found that this fly line contains a null mutation in the dredd gene, a component of the immune deficiency (Imd) pathway required to resist Gramnegative bacterial infection[7,30] (Supplementary Fig. 2a–d) Mutations with such a strong loss-of-function phenotype tend to be rare in a natural population and do not capture most of the underlying natural variation in gut immunocompetence[20]. These results suggest that the DGRP phenotypes observed for P. entomophila infection may reflect a more general pattern in that they may be due to a common, likely bacterium-independent genetic and molecular mechanism that mediates oral infection susceptibility
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