Growth phase influences virulence in <i>Candidozyma auris</i> systemic infection models

<i>Candidozyma auris</i> is a growing public health concern, capable of causing long-term contamination of healthcare settings, skin colonization, and life-threatening bloodstream infections. However, <i>C. auris</i> pathogenesis is not well understood, which is exacerbated by limitations and discrepancies in existing animal infection models. Further, the effects of <i>C. auris</i> 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-phase and stationary-phase <i>C. auris</i> systemic infection in immunocompetent C57BL/6J mice at high and low doses of infection. Systemic infection with high-dose log-phase <i>C. auris</i> results in rapid mortality between 2 h and 1 day post-infection, whereas stationary phase <i>C. auris</i> results in significantly extended survival. However, at low doses of infection, there was no difference in mortality kinetics between log-phase and stationary-phase cells. We observed that <i>C. auris</i> 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 <i>C. auris</i> 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 β-glucan exposure and mannan abundance in log-phase <i>C. auris</i>. These results will inform the development of a more standardized animal model of systemic <i>C. auris</i> infection, which can be used to reveal key aspects of <i>C. auris</i> pathogenesis.IMPORTANCEDespite its growing medical importance, there is limited understanding of <i>Candidozyma auris</i> pathogenesis, due in part to limitations of existing laboratory models of infection. To develop a more complete understanding of factors that contribute to <i>C. auris</i> 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 <i>C. auris</i> 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-phase or stationary-phase <i>C. auris</i>, suggesting that growth phase can affect <i>C. auris</i> pathogenesis. These differences correlated with increased exposure of pathogen-associated molecular patterns in the <i>C. auris</i> cell wall in log-phase cells. These results will be instrumental in the future development of standardized animal models to study <i>C. auris</i> pathogenesis.