Iron sequestration by transferrin 1 mediates nutritional immunity inDrosophila melanogaster

Abstract

Iron sequestration is a recognized innate immune mechanism against invading pathogens mediated by iron-binding proteins called transferrins. Despite many studies on antimicrobial activity of transferrins in vitro, their specific in vivo functions are poorly understood. Here we use Drosophila melanogaster as an in vivo model to investigate the role of transferrins in host defense. We find that systemic infections with a variety of pathogens trigger a hypoferremic response in flies, namely, iron withdrawal from the hemolymph and accumulation in the fat body. Notably, this hypoferremia to infection requires Drosophila nuclear factor κB (NF-κB) immune pathways, Toll and Imd, revealing that these pathways also mediate nutritional immunity in flies. Next, we show that the iron transporter Tsf1 is induced by infections downstream of the Toll and Imd pathways and is necessary for iron relocation from the hemolymph to the fat body. Consistent with elevated iron levels in the hemolymph, Tsf1 mutants exhibited increased susceptibility to Pseudomonas bacteria and Mucorales fungi, which could be rescued by chemical chelation of iron. Furthermore, using siderophore-deficient Pseudomonas aeruginosa, we discover that the siderophore pyoverdine is necessary for pathogenesis in wild-type flies, but it becomes dispensable in Tsf1 mutants due to excessive iron present in the hemolymph of these flies. As such, our study reveals that, similar to mammals, Drosophila uses iron limitation as an immune defense mechanism mediated by conserved iron-transporting proteins transferrins. Our in vivo work, together with accumulating in vitro studies, supports the immune role of insect transferrins against infections via an iron withholding strategy.

Parasite Presence Induces Gene Expression Changes in an Ant Host Related to Immunity and Longevity

“…The gene with the highest contribution was encoding a bromodomain-containing protein, an epigenetic reader ( Supplementary Materials, Figure S2 ), with a role in inflammation and cancer in humans [ 76 ]. Transferrin is a key player in iron metabolism, and previous work in insects suggests that it is also involved in immune response [ 77 ]. It was also one of the few genes involved in immunity found to be upregulated in the brains of infected workers [ 23 ].…”

The receptor kinase SRF3 coordinates iron-level and flagellin dependent defense and growth responses in plants

“…We show that SRF3 transduces signals that lead to a coordinated response of root growth regulation, iron homeostasis and bacterial immunity through its modulation of callose synthase-dependent signaling. Because this is highly reminiscent of nutritional immunity conferred by the TfR mammalian and Drosophila systems that sense iron levels and control iron and immune responses, we propose that SRF3 is instrumental in mediating plant nutritional immunity (Cassat and Skaar, 2013;Iatsenko et al, 2020).…”

Dual proteomics ofDrosophila melanogasterhemolymph infected with the heritable endosymbiontSpiroplasma poulsonii

“…Gene expression measurement were performed by RT-qPCR as previously described (Iatsenko et al, 2020; Romeo and Lemaitre, 2008). Briefly, 10 whole flies were crushed and their RNA extracted with the Trizol method.…”