AbstractBackgroundResistance to enteric pathogens is a complex trait at the crossroads of multiple biological processes. We have previously shown in theDrosophilaGenetic Reference Panel (DGRP) that resistance to infection is highly heritable, but our understanding of how the effects of genetic variants affect different molecular mechanisms to determine gut immunocompetence is still limited.ResultsTo address this, we perform a systems genetics analysis of the gut transcriptomes from 38 DGRP lines that were orally infected withPseudomonas entomophila. We identify a large number of condition-specific, expression quantitative trait loci (local-eQTLs) with infection-specific ones located in regions enriched for FOX transcription factor motifs. By assessing the allelic imbalance in the transcriptomes of 19 F1 hybrid lines from a large round robin design, we independently attribute a robustcis-regulatory effect to only 10% of these detectedlocal-eQTLs. However, additional analyses indicate that manylocal-eQTLs may act intransinstead. Comparison of the transcriptomes of DGRP lines that were either susceptible or resistant toPseudomonas entomophilainfection revealsnutcrackeras the only differentially expressed gene. Interestingly, we find thatnutcrackeris linked to infection-specific eQTLs that correlate with its expression level and to enteric infection susceptibility. Further regulatory analysis reveals one particular eQTL that significantly decreases the binding affinity for the repressor Broad, driving differential allele-specificnutcrackerexpression.ConclusionsOur collective findings point to a large number of infection-specificcis-andtrans-acting eQTLs in the DGRP, including one common non-coding variant that lowers enteric infection susceptibility.