Growth phase influences virulence in Candida auris systemic infection models

Abstract

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.