Tornadic shear stress induces a transient, calcineurin-dependent hyper-virulent phenotype in Mucorales molds

摘要: Abstract Trauma-related necrotizing myocutaneous mucormycosis (NMM) has a high morbidity and mortality in victims of combat-related injuries, geo-meteorological disasters, severe burns. Inspired by the observation that several recent clusters NMM have been associated with extreme mechanical forces (e.g. during tornados), we studied impact stress on Mucoralean biology virulence Drosophila melanogaster infection model. In contrast to other experimental procedures exert stress, tornadic shear challenge (TSC) magnetic stirring induced hyper-virulent phenotype clinically relevant Mucorales species but not Aspergillus or Fusarium. Whereas fungal growth rates, morphogenesis, susceptibility noxious environments phagocytes were altered TSC, soluble factors released supernatant shear-challenged R. arrhizus spores rendered static hyper-virulent. Consistent rapid decay TSC-induced hyper-virulence, minimal transcriptional changes revealed comparative RNA sequencing analysis Rhizopus arrhizus. However, inhibition calcineurin/heat shock protein 90 (hsp90) response circuitry cyclosporine A (CsA) tanespimycin abrogated increased pathogenicity following TSC. Similarly, calcineurin loss-of-function mutants Mucor circinelloides displayed no capacity flies after undergoing Collectively, these results establish TSC induces hyper-virulence specifically point out calcineurin/hsp90 pathway as key orchestrator this phenotype. Our findings invite future studies topical inhibitor treatment wounds an adjunct mitigation strategy for high-energy trauma. Significance Given limited efficacy current medical treatments trauma-related mucormycosis, there is dire need better understand pathophysiology order develop novel strategies counteract tissue invasion Here, describe transiently various pathogenic molds known cause wound infections. data support model whereby stress-induced primarily driven orchestrated pathway. Importantly, pharmacological genetic signaling stress-challenged Mucorales, encouraging further evaluation (topical) inhibitors improve therapeutic outcomes blast injuries violent storms.