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The interaction ofCandida albicans with the innate immune system is the key determinant of the pathogen/commensal balance and has selected for adaptations that facilitate the utilization of nutrients commonly found within the host, including proteins and amino acids; many of the catabolic pathways needed to assimilate these compounds are required for persistence in the host. We have shown thatC. albicans co-opts amino acid catabolism to generate and excrete ammonia, which raises the extracellular pH, bothin vitro andin vivo and induces hyphal morphogenesis. Mutants defective in the uptake or utilization of amino acids, such as those lackingSTP2 , a transcription factor that regulates the expression of amino acid permeases, are impaired in multiple aspects of fungus-macrophage interactions resulting from an inability to neutralize the phagosome. Here we identified a novel role in amino acid utilization for Ahr1p, a transcription factor previously implicated in regulation of adherence and hyphal morphogenesis. Mutants lackingAHR1 were defective in growth, alkalinization, and ammonia release on amino acid-rich media, similar tostp2 Δ andahr1 Δstp2 Δ cells, and occupied more acidic phagosomes. Notably,ahr1 Δ andstp2 Δ strains did not induce pyroptosis, as measured by caspase-1-dependent interleukin-1β release, though this phenotype could be suppressed by pharmacological neutralization of the phagosome. Altogether, we show thatC. albicans -driven neutralization of the phagosome promotes hyphal morphogenesis, sufficient for induction of caspase-1-mediated macrophage lysis.

Phagosomal Neutralization by the Fungal Pathogen Candida albicans Induces Macrophage Pyroptosis