IbinA and IbinB regulate the Toll pathway-mediated immune response inDrosophila melanogaster
Abstract
To combat infection, an immune system needs to be promptly activated but tightly controlled to avoid destructive effects on host tissues. IbinA and IbinB are related short peptides with robust expression upon microbial challenge inDrosophila melanogaster. Here, we show thatIbingenes are ubiquitously present in flies of theDrosophilasubgenusSophophora, where they replace a different but probably related gene,Mibin, which is found across a much wider range of cyclorrhaphan flies. Using synthetic peptides, we did not observe any direct bactericidal or bacteriostatic activity for either IbinA or IbinBin vitro. Using mutantDrosophilalines lacking theIbinAgene,IbinBgene, or both, we examined their roles in development and during microbial infections.IbinAis expressed in early pupae, and a lack ofIbinAandIbinBleads to temperature-dependent formation of melanized tissue during metamorphosis, frequently around the trachea. IbinA and IbinB have distinct effects on susceptibility to microbial infection. For example,IbinBmutant flies, as well as flies lacking bothIbinAandIbinB, had improved survival when challenged withListeria monocytogenes, an intracellular pathogen, whereas a lack ofIbinAalone had no effect. RNA sequencing of wildtype and mutant flies infected withL. monocytogenesshowed enhanced Toll target gene expression in flies lackingIbinB, suggesting that IbinB acts as a negative regulator of the Toll pathway. In contrast,IbinAmutants had decreased Toll target gene expression in this context. Correspondingly,IbinBmutant flies had improved andIbinA compromised survival in septic fungal infection, where the Toll pathway has a major role. Our study provides insight into the roles of IbinA and IbinB in regulation of the immune response inDrosophila.
Author summary
While the immune systems of animals must be able to be rapidly activated, they have the potential to cause severe tissue damage when overactive.Drosophila melanogasterhas proven to be a highly effective model for studying core immune system pathways, and for developing concepts in host-pathogen interactions. The main signaling pathways involved in activation of theDrosophilaimmune system are well described and have contributed to the discovery of homologous pathways in the mammalian immune system. Despite this, the molecular mechanisms of action of the genes expressed downstream of these pathways are generally not well characterized. Regulation of the immune response also requires further investigation. Here, we useDrosophilamutants to show roles for two short peptides, both highly expressed during infection. IbinA and IbinB regulate the humoral immune response and the melanization reaction (an insect-specific immune reaction against parasites). Flies lacking one or both of these genes mount a stronger, more effective response to some pathogenic bacteria compared to wild type flies. During development, IbinA and IbinB have tissue protective roles, with mutants showing tissue damage due to aberrant immune activation. Our results indicate that IbinA and IbinB are important regulators of the immune response with tissue protective properties.
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