Sex differences in <i>Drosophila</i> intestinal metabolism contribute to sexually dimorphic infection outcome and alter gut pathogen virulence.

Abstract

Sexual dimorphism in infection outcomes is widespread, yet its underlying mechanisms remain incompletely understood. Utilizing <i><i>Pseudomonas</i> entomophila</i> intestinal infection in <i>Drosophila,</i> we demonstrate that sex differences in intestinal redox processes contribute to female-biased susceptibility to infection. Female inability to overcome pathogen-induced oxidative stress results in defecation blockage, pathogen persistence, and host death. Male flies exhibit increased carbohydrate metabolism and pentose phosphate pathway activity-a key antioxidant defense system. This allows males to withstand oxidative stress-induced defecation blockage and clear the pathogen from the intestine, resulting in survival. Notably, we uncovered that Duox-dependent processes contribute to pathology independently of total ROS levels. In parallel, <i>P. entomophila</i> showed increased expression of several virulence factors, including RNA-binding protein Hfq, in the female gut, contributing to female-biased virulence of <i>P. entomophila</i>. Thus, the effect of the gut metabolic environment on host defenses and pathogen virulence determines the sex differences in intestinal infection outcomes.