Candida albicans rvs161 Δ and rvs167 Δ Endocytosis Mutants Are Defective in Invasion into the Oral Cavity

Invasive growth in tissues by the human fungal pathogen is promoted by a switch from budding to hyphal morphogenesis that is stimulated by multiple environmental factors that can vary at different sites of infection. To identify genes that promote invasive growth in the oral cavity to cause oropharyngeal candidiasis (OPC), we first identified mutants that failed to invade agar medium. Analysis of nine severely defective mutants in a mouse model of OPC revealed that the strongest defects were seen for the Δ and Δ mutants, which lack amphiphysin proteins needed for endocytosis. The Δ mutants initially adhered to the tongue but failed to invade efficiently and were lost from the oral cavity. Previous studies indicated that Δ mutants formed filamentous hyphae in the kidney albeit with morphological abnormalities, suggesting that the Δ mutants were influenced by factors that vary at different sites of infection. Consistent with this, increasing concentrations of CO , an inducer of hyphal growth that is more abundant in internal organs than air, partially rescued the invasive-growth defects of the Δ mutants Interestingly, preinduction of the Δ mutants to form hyphae prior to introduction into the oral cavity restored their ability to cause OPC, identifying a key role for endocytosis in initiating invasive hyphal growth. These results highlight the influence of distinct environmental factors in promoting invasive hyphal growth in the oral cavity and indicate that blocking endocytosis could have therapeutic value in preventing the initiation of OPC. Oropharyngeal candidiasis (OPC) is a common fungal infection that is associated with severe morbidity. Another concern is that patients at risk for developing OPC often take long courses of antifungal drugs, which can lead to the emergence of drug-resistant strains. We therefore identified nine mutants with defects in undergoing invasive hyphal growth in the oral cavity, increasing the number of genes known to be involved in OPC by more than 30%. The two strongest mutants, Δ and Δ, have defects in endocytosis. The Δ mutants appear to have a specific defect in initiating invasive growth, as preinducing the cells to form hyphae prior to infection restored their ability to cause OPC. These results indicate that blocking endocytosis could have therapeutic value in preventing the initiation of OPC without leading to development of resistance against drugs currently used to treat fungal infections.