Negative immune regulation contributes to disease tolerance in <i>Drosophila melanogaster</i>

Abstract Disease tolerance is an infection phenotype where hosts show relatively high health despite harbouring elevated pathogen loads. Variation in the ability to reduce immunopathology may explain why some hosts can tolerate higher pathogen burdens with reduced pathology. Negative immune regulation would therefore appear to be a clear candidate for a mechanism underlying disease tolerance. Here, we examined how the negative regulation of the immune deficiency (IMD) pathway affects disease tolerance in Drosophila melanogaster when infected with four doses of the gram‐negative bacterial pathogen Pseudomonas entomophila . We find that while flies unable to regulate the IMD response exhibited higher expression of antimicrobial peptides and lower bacterial loads as expected, this was not accompanied by a proportional reduction in mortality. Instead, ubiquitous UAS‐RNAi knockdown of negative regulators of IMD ( pirk and caudal ) substantially increased the per‐pathogen‐mortality in both males and females across all tested infectious doses. Our results therefore highlight that in addition to regulating an efficient pathogen clearance response, negative regulators of IMD also contribute to disease tolerance.