Deconstructing pathogen-symbiont interactions in the Drosophila model

The interactions between pathogens and resident microbes that colonize host tissues are an inevitable component of many infections, with dramatic consequences for disease outcomes. Despite the clear importance of understanding these interactions, our knowledge still remains limited. We utilize the fruit fly Drosophila melanogaster, taking advantage of its extensive genetic toolkit, evolutionarily conserved innate immune defenses, and manipulable microbiome as a model to decipher how host-microbe and microbe-microbe interactions influence infection outcomes. Recently, we focused on the impact of infection on Drosophila microbiota and found that gut communities remain resilient to infection-induced immune response. We discovered that intrinsic resistance to host antimicrobial peptides (AMPs) is a key mechanism that mediates such resilience. By transposon screening in Lactiplantibacillus plantarum, a major Drosophila commensal, we identified several mutants sensitive to AMPs. These mutants were impaired in cell wall-modifying enzymes, resulting in increased negative cell surface charge and higher affinity to cationic AMPs. AMP-sensitive mutants were cleared from the gut after infection in wild-type, but not in AMP-deficient flies, suggesting that resistance to host AMPs is essential for commensal resilience in an inflamed gut environment. Additionally, we found that L. plantarum even benefits from infection-induced perturbations by increasing in abundance. We identified infection-induced glycosaminoglycan remodelling as one of the underlying mechanisms. Specifically, infection leads to an increased synthesis of heparan sulfate, which promotes L. plantarum adhesion and biofilm formation. This finding represents an intriguing example of how certain commensals benefit from the infection-induced metabolic remodelling, in turn providing colonization resistance to the host.