Davis, F. A. | bioRxiv Science

bioRxiv2025

Bacterial metabolites induce cell wall remodeling, antifungal resistance, and immune recognition of commensal fungi

The fungus Candida albicans commensally colonizes mucosal surfaces in healthy individuals but can cause both superficial mucosal and life-threatening disseminated infections. The balance between commensalism and pathogenicity is complex and depends on factors including host and fungal genetic background, the host environment, and fungal interactions with local microbes. The major interaction interface of C. albicans with the host is its multilayered cell wall, which is dynamic and highly responsive to the surrounding environment. Therefore, factors that influence the fungal cell wall will directly impact C. albicans-host interactions. Our work demonstrates that multiple physiologically-relevant gastrointestinal bacteria influence fungal cell wall composition during co-culture with C. albicans, including as complex communities derived from the gut. Using Escherichia coli as a model, we show that bacterial-induced fungal cell wall remodeling occurs rapidly and is mediated by secreted bacterial metabolite(s). Fungal mutant analysis revealed that the high osmolarity glycerol (HOG) pathway, which is critical for responding to environmental stresses, has an important role in regulating this cell wall remodeling phenotype through the Sln1 histidine kinase. Importantly, bacterial-mediated fungal cell wall remodeling increases C. albicans resistance to the echinocandins, increases recognition by both dectin-1 and dectin-2, and decreases recognition by human IgA. Overall, this work comprehensively characterizes an interaction between C. albicans and common gastrointestinal bacteria that has important implications for fungal biology and host interactions.

microbiology↗

bioRxiv2025

Growth phase influences virulence in Candida auris systemic infection models

Candidozyma auris is a growing public health concern, capable of causing long-term contamination of healthcare settings, skin colonization, and life-threatening bloodstream infections. However, C. auris pathogenesis is not well understood, which is exacerbated by limitations and discrepancies in existing animal infection models. Further, the effects of C. auris growth phase on virulence have not been examined, despite growth phase being linked to virulence in many bacterial species. To address this question, and to develop an immunocompetent murine model of infection, we directly compared log and stationary phase C. auris systemic infection in immunocompetent C57BL/6J mice at high and low doses of infection. Systemic infection with high dose log phase C. auris results in rapid mortality between 2 hours and 1 day post infection, whereas stationary phase C. auris results in significantly extended survival. However, at low doses of infection, there was no difference in mortality kinetics between log and stationary phase cells. We observed that C. auris initially colonizes multiple organs but is rapidly cleared from the lungs and spleen, while kidney fungal burdens remain stable. Mice infected with high dose log phase C. auris had Fibrin-associated blood clotting in multiple organs and decreased serum Fibrinogen levels, suggesting that coagulation may drive rapid mortality. This was associated with increased {beta}-glucan exposure and mannan abundance in log phase C. auris. These results will inform the development of a more standardized animal model of systemic C. auris infection, which can be used to reveal key aspects of C. auris pathogenesis. ImportanceDespite its growing medical importance, there is limited understanding of Candidozyma auris pathogenesis, due in part to limitations of existing laboratory models of infection. To develop a more complete understanding of factors that contribute to C. auris pathogenesis, it will be necessary to establish consistent parameters for animal models of infection. To address this need, we directly compared log and stationary growth phases on C. auris pathogenesis in immunocompetent C57BL/6J mice using a single virulent Clade I isolate. At a high dose of infection, host survival was dramatically different between log or stationary phase C. auris, suggesting that growth phase can affect C. auris pathogenesis. These differences correlated with increased exposure of pathogen-associated molecular patterns in the C. auris cell wall in log phase cells. These results will be instrumental in the future development of standardized animal models to study C. auris pathogenesis.

microbiology↗