Sex Bias in Iron Sequestration by Transferrin 1 Modulates Sexually-Dimorphic Infection Outcomes in Drosophila melanogaster

Host sexual dimorphism in the outcome of infections is a ubiquitous phenomenon across taxa. However, the immunological differences between males and females and the mechanisms underlying them remain poorly characterized. Here, we used Drosophila melanogaster to test the hypothesis that sex differences in nutritional immunity, particularly iron sequestration, contribute to sexual dimorphism in infection outcome. Using the natural Drosophila pathogen Providencia alcalifaciens, which is controlled by host-mediated iron sequestration, we established an infection model in which males demonstrate increased resistance. Leveraging this model, we demonstrated that males exhibit higher basal and infection-induced expression levels of Transferrin 1-an iron transporter mediating iron sequestration during infection. Consequently, males contained lower iron levels in the hemolymph compared to females. Importantly, sex differences in iron content and in survival after P. alcalifaciens infection were abolished in Tsf1 mutants. However, these mutants still exhibited sex differences in pathogen load. Thus, while Tsf1 mediates sexual dimorphism in iron sequestration and susceptibility to P. alcalifaciens infection, it also has an unexpected role in host tolerance to infection. Finally, we demonstrated that the Toll pathway mediates sex differences in Tsf1 expression and susceptibility to infection. Altogether, our study demonstrates that Tsf1-mediated iron sequestration differs between male and female D. melanogaster, thereby identifying nutritional immunity as a determinant of sexual dimorphism in infection outcome.