Malassezia and Candida auris: skin microbiome dysbiosis and de-regulation of cutaneous homeostasis

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Abstract Malassezia yeasts are lipophilic and are the most abundant fungi of the skin microbiome of warm- blooded animals. In addition to a commensal lifestyle, Malassezia yeasts are associated with skin diseases and also bloodstream infection. Studies have linked Malassezia in the GI tract as a risk factor for Crohn's Disease in patients with CARD9 mutations and potentially in pancreatic cancer progression, whereas Malassezia in the lung has been linked to Cystic Fibrosis exacerbation. In parallel, Candida auris has emerged globally and is frequently drug-resistant and increasingly causing hospital-acquired skin colonization with significant risk of systemic infection with significant morbidity and mortality. Julie Segre and colleagues have developed a mouse model of Candida auris colonization and found that human skin mycobiome dysbiosis, likely caused by antibiotics and antifungal drugs, shifts skin colonization from Malassezia-dominant to Candida-species dominant patterns prior to Candida auris systemic infections. Genetic and genomics studies from our group and others have advanced the state of the art for the study of Malassezia species and their interactions with bacteria and fungi in the skin microbiome and the host. We developed an Agrobacterium tumefaciens approach enabling generation of both random and targeted mutants of two Malassezia species, and applied these tools to study functions of Malassezia genes with roles in drug action and host-pathogen interactions. We have conducted extensive genomic analysis, contributing genome annotation via proteomics and obtaining complete telomere-telomere, well-annotated Malassezia reference genomes. Our past studies on Candida species defined a globally conserved role of calcineurin in fungal pathogenesis, advanced genomics across the Candida pathogenic species complex, and documented that Candida lusitaniae, closely related to Candida auris, has a complete sexual cycle. Our key collaborator Salome LeibundGut-Landmann has developed a murine skin model for Malassezia integral to these studies. Here we propose to study the interactions of Malassezia with Candida auris in dysbiosis of the skin microbiome as a risk factor for systemic infection. In Aim 1 we propose to focus on 1) a novel dsRNA Malassezia mycovirus we discovered and its encoded candidate protein effector by generating and studying strains cured of either or both viral RNAs, and 2) Malassezia secreted proteins (including allergens and proteases) by studying gene deletion mutants as well as random insertion mutants. In Aim 2, Malassezia virus-infected, virus-semi-cured, and virus-cured strains and mutants generated in Aim 1 will be studied with in vitro and in vivo models to define molecular mechanisms of interactions with Candida auris and the host. The studies proposed will advance the field, providing insights as a foundation for studies aiming to elucidate the beneficial roles Malassezia plays as skin commensals that protect the human host from systemic infection by fungal pathogens through competitive and exclusive colonization of the skin microenvironment.