A novel mycovirus evokes transcriptional rewiring in the fungusMalasseziaand stimulates interferon-β production in macrophages
Authors: Clancey Shelly Applen , Ruchti Fiorella , LeibundGut-Landmann Salomé , Heitman Joseph , Ianiri Giuseppe 
Published: December 2019

AbstractMycoviruses infect fungi, and while most persist asymptomatically, there are examples of mycoviruses having both beneficial and detrimental effects on their host. Virus-infectedSaccharomycesandUstilagostrains exhibit a killer phenotype conferring a growth advantage over uninfected strains and other competing yeast species, whereas hypovirus-infectedCryphonectria parasiticadisplays defects in growth, sporulation, and virulence. In this study we identify a dsRNA mycovirus in fiveMalasseziaspecies. Sequence analysis reveals it to be a totivirus with two dsRNA segments: a larger 4.5 kb segment with genes encoding components for viral replication and maintenance, and a smaller 1.4 kb segment encoding a novel protein. Furthermore, RNA-seq of virus-infected versus virus-curedMalassezia sympodialisrevealed an upregulation of dozens of ribosomal components in the cell, suggesting the virus modifies the transcriptional and translational landscapes of the cell. Given thatMalasseziais the most abundant fungus on human skin, we assessed the impact of the mycovirus in a murine epicutaneous infection model. Although infection with virus-infected strains was not associated with an increased inflammatory response, we did observe enhanced skin colonization in one of two virus-infectedM. sympodialisstrains. Noteworthy, interferon-β expression was significantly upregulated in bone marrow-derived macrophages when challenged with virus-infected, compared to virus-curedM. sympodialis, suggesting that the presence of the virus can induce an immunological response. Although many recent studies have illuminated how widespread mycoviruses are, there are relatively few in-depth studies about their impact on disease caused by the host fungus. We describe here a novel mycovirus inMalasseziaand its possible implications in pathogenicity.ImportanceMalasseziaspecies represent the most common fungal inhabitant of the mammalian skin microbiome, and are natural skin commensal flora. However, these fungi are also associated with a variety of clinical skin disorders. Recent studies have reported associations ofMalasseziawith Crohn’s disease and pancreatic cancer, further implicating this fungal genus in inflammatory and neoplastic disease states. BecauseM. sympodialishas lost genes involved in RNAi, we hypothesizedMalasseziacould harbor dsRNA mycoviruses. Indeed, we identified a novel mycovirus of the totivirus family in severalMalasseziaspecies, and characterized the MsMV1 mycovirus ofM. sympodialis. We found conditions that lead to curing of the virus, and analyzed isogenic virus-infected/virus-cured strains to determine MsMV1 genetic and pathogenic impacts. MsMV1 induces a strong overexpression of transcription factors and ribosomal genes, while downregulating cellular metabolism. Moreover, MsMV1 induced a significantly higher level of interferon-β expression in cultured macrophages. This study sheds light on the mechanisms of pathogenicity ofMalassezia, focusing on a previously unidentified novel mycovirus.