A bacterial endosymbiont enables fungal immune evasion during fatal mucormycete infection

Abstract Environmentally ubiquitous fungal spores of the Mucorales order cause acute invasive infections through germination and evasion of the mammalian host immune system. Early phagocyte control of spore germination plays a key role in controlling infection, yet swelling Mucorales spores evade phagocytosis through an unknown mechanism. Here we investigate fungal immune evasion in a clinical isolate of Rhizopus microsporus and reveal the role of a bacterial endosymbiont, Ralsonia pickettii , in fungal pathogenesis. Analysis of phagocytosis rates in wild type and cured fungal isolates demonstrates a role for the endosymbiont in immune cell evasion through disruption of the cytoskeleton and phagosome maturation. Further analysis of bacterial secreted products revealed the presence of a previously uncharacterized secondary metabolite whose production is induced by the presence of the fungus. Analysis of the bacterial genome and condition-dependent RNAseq implicate a cryptic type I polyketide synthase. Subsequent analysis of wild type and cured spores in a zebrafish larvae model of infection demonstrate a role for the endosymbiont in suppressing macrophage and neutrophil recruitment to the site of infection. Finally, we demonstrate that this has implications for fungal clearance in an immunocompetent murine model of infection. Together, these findings identify for the first time a role for a bacterial endosymbiont in the pathogenesis of Rhizopus microsporus during animal infection.