The iron transporter Transferrin 1 mediates homeostasis of the endosymbiotic relationship between Drosophila melanogaster and Spiroplasma poulsonii.

Iron is involved in numerous biological processes in both prokaryotes and eukaryotes and is therefore subject to a tug-of-war between host and microbes upon pathogenic infections. In the fruit fly Drosophila melanogaster, the iron transporter Transferrin 1 (Tsf1) mediates iron relocation from the hemolymph to the fat body upon infection as part of the nutritional immune response. The sequestration of iron in the fat body renders it less available for pathogens, hence limiting their proliferation and enhancing the host ability to fight the infection. Here we investigate the interaction between host iron homeostasis and Spiroplasma poulsonii, a facultative, vertically transmitted, endosymbiont of Drosophila. This low-pathogenicity bacterium is devoid of cell wall and is able to thrive in the host hemolymph without triggering pathogen-responsive canonical immune pathways. However, hemolymph proteomics revealed an enrichment of Tsf1 in infected flies. We find that S. poulsonii induces tsf1 expression and triggers an iron sequestration response similarly to pathogenic bacteria. We next demonstrate that free iron cannot be used by Spiroplasma while Tsf1-bound iron promotes bacterial growth, underlining the adaptation of Spiroplasma to the intra-host lifestyle where iron is mostly protein-bound. Our results show that Tsf1 is used both by the fly to sequester iron and by Spiroplasma to forage host iron, making it a central protein in endosymbiotic homeostasis.