Iron sequestration by transferrin 1 mediates nutritional immunity in <i>Drosophila melanogaster</i>

Significance Hosts sequester iron as a strategy to limit pathogen acquisition of this essential nutrient in a process termed nutritional immunity. Due to their in vitro antimicrobial activity, iron-binding proteins transferrins are suspected to play a role in iron sequestration. However, little is known about the in vivo role of transferrins. Here, we found that Drosophila melanogaster exhibits infection-induced hypoferremia mediated by Transferrin 1. Due to excessive iron in hemolymph, Transferrin 1 ( Tsf1 )-deficient flies are hypersusceptible to certain infections. Our study reveals that nutritional immunity is an important, previously unrecognized arm of immune defense in Drosophila . Using fly and bacterial genetics, we show that Tsf1 mediates nutritional immunity by sequestering iron from the pathogens in vivo on the whole-organism level.