Respiration supports intraphagosomal filamentation and escape of Candida albicans from macrophages

For the human fungal pathogen Candida albicans, metabolic flexibility and the ability to transition between yeast and filamentous growth states are key virulence traits that enable disease in the host. These traits are particularly important during the interaction of C. albicans with macrophages, where the fungus must utilize multiple alternative carbon sources to survive after being phagocytosed, and filamentation is coupled to fungal escape and immune cell death. Here, we employed functional genomic screening of conditional-expression mutants covering >50% of the C. albicans genome to identify genes selectively required for filamentation inside macrophages. Through manual and machine learning-based image analyses, we uncovered a role for the mitochondrial ribosome, respiration, and the SNF1 AMP-activated kinase complex in governing filamentous growth within the phagosome, suggesting that C. albicans relies on respiration to evade the antifungal activities of macrophages. We demonstrate that downregulating the expression of these genes reduces ATP levels and impedes filamentation as well as growth under monoculture conditions in medium lacking glucose. In co-culture with physiological glucose concentration, downregulation of genes involved in mitochondrial function and respiration prevented C. albicans from expanding within the phagosome, escaping, and inducing immune cell death. Together, our work provides new insights into the impact of metabolism on the interaction between C. albicans and macrophages, highlighting respiration and the SNF1 AMP-activated kinase as key effectors of C. albicans metabolic flexibility and filamentation within phagocytes.