Bruno Lemaitre, Alice Marra and Florent Masson: microLife article award 2021
Bruno Lemaitre, Alice Marra and Florent Masson wrote the excellent paper “The iron transporter Transferrin 1 mediates homeostasis of the endosymbiotic relationship between Drosophila melanogaster and Spiroplasma poulsonii” in our journal microLife. This was selected by the microLife Editors-in-Chief as the best 2021 article!
We interviewed all the authors to find out more about the inspiration behind this paper:
Could you provide a bit of context into what Transferrin 1 is?
Iron is an essential micronutrient for all living organisms. In the case of an infection with microbes, both the host and the pathogen need iron and compete for it. Iron sequestration by the host (i.e. moving iron from the extracellular space, where pathogens can access it, towards the intracellular space) is a powerful defense mechanism that prevents pathogen proliferation, a process called “nutritional immunity”. Iron sequestration is mediated by iron-binding proteins called transferrins and their function and structure are extremely well conserved among eukaryotic species.
Transferrin 1 (Tsf1) is a Drosophila melanogaster iron binding transporter involved in the iron homeostasis. In uninfected flies, it transports iron between tissues to ensure its proper distribution during development and adult life. Recent data from our lab showed that it is induced upon acute pathogenic infections and participates in the nutritional defense by sequestering iron in the fly fat body (the analogous of mammalian liver). This pushed us to investigate Tsf1 function during symbiotic infections that are long-lasting, non-pathogenic infections.”
Could you provide a brief, simple overview of the topic your paper covers?
To address this, we used as a model the Drosophila-Spiroplasma interaction. Spiroplasma poulsonii is the second most widespread bacterial endosymbiont in insects and naturally infects Drosophila melanogaster in the wild. Spiroplasma lives extracellular in the fly hemolymph where it scavenges host nutrients (notably lipids). It hijacks the fly oogenesis to gain access to the developing oocytes and be vertically transmitted, which creates a stable interaction over evolutionary time. Intriguingly, Spiroplasma has no cell wall and does not trigger the canonical immune response of the fly. Yet the bacterial titer is tightly controlled in the fly hemolymph, which suggests that other factors are involved in keeping the symbionts in check.
In our work we investigated the role of host iron metabolism and of the iron binding protein Tsf1 in the frame of Drosophila-Spiroplasma interaction. We hypothesized that Spiroplasma could be controlled by nutritional immunity just like pathogens are during acute infections.
We showed that the tsf1 gene is upregulated upon Spiroplasma infection, and that this upregulation is associated with a sequestration of iron from the hemolymph towards the fat body. This process is reminiscent of the role of Tsf1 in nutritional immunity against pathogenic infections. Furthermore, we used Tsf1 loss-of-function mutant flies to show that Spiroplasma actually relies on host Tsf1 to sustain its on growth: Indeed, the symbionts can uptake iron only when bound to Drosophila Tsf1 (and not, for example, bound to a mammal analogue). This indicates that the fly mounts a nutritional response against the symbiont, and that in turn the symbiont takes advantage of it to sustain its own growth.
Overall, this work identifies a new growth-limiting factor involved in Spiroplasma-Drosophila symbiotic homeostasis and a new function for transferrins in the context of insect symbiosis.”
What encouraged you to perform research this area of microbiology?
Because Spiroplasma is unique! This bacterium gets passed from mother to offspring across generations and lives free within insect tissues without triggering any adverse response from its host. There are also a lot of fascinating side-effects to such infection that we didn’t mention. For example, infected mothers have only daughters because of a reproduction manipulation phenotype called male-killing. There are also positive side-effects, for example infected flies and larvae are protected against natural enemies such as nematodes and parasitoid wasps.
The list of Spiroplasma weird kinks is long and there is so much we still don’t know about this symbiont, especially when it comes to molecular mechanisms. This is what makes Spiroplasma symbiosis a thrilling model in microbiology.”
What do you see as the next steps in this area of research?
We identified Tsf1 as an important actor of the nutritional immune response against Spiroplasma, but there have to be plenty of others and notably other proteins involved in iron homeostasis. For example, iron-complexed protein in mammals are internalized in host cells upon binding to specialized receptors. However, none of these have been found in Drosophila, so we know which protein transports iron to the cell but we have no idea how it crosses the membrane and how Spiroplasma interacts with this process. Further investigations should also clarify the mechanism of uptake of Tsf1-bound iron by Spiroplasma. Does Tsf1 enter the Spiroplasma cell? Are iron ions captured by bacterial siderophores?
Last but not least, we do not know how the tsf1 gene is induced upon Spiroplasma infection. Our lab recently showed that tsf1 transcription is regulated by host immune pathways that can sense peptidoglycan. But… Spiroplasma has no cell wall and, as such, no peptidoglycan. Yet it triggers a strong and chronic upregulation of tsf1, which suggests that there is a tsf1 induction mechanism that we totally ignore and that could have important function beyond symbiosis.”
Read the 2021 award winning paper: The iron transporter Transferrin 1 mediates homeostasis of the endosymbiotic relationship between Drosophila melanogaster and Spiroplasma poulsonii