Diverse mechanisms control amino acid‐dependent environmental alkalization by Candida albicans

Abstract

AbstractCandida albicans has the capacity to neutralize acidic growth environments by releasing ammonia derived from the catabolism of amino acids. The molecular components underlying alkalization and its physiological significance remain poorly understood. Here, we present an integrative model with the cytosolic NAD+‐dependent glutamate dehydrogenase (Gdh2) as the principal ammonia‐generating component. We show that alkalization is dependent on the SPS‐sensor‐regulated transcription factor STP2 and the proline‐responsive activator Put3. These factors function in parallel to derepress GDH2 and the two proline catabolic enzymes PUT1 and PUT2. Consistently, a double mutant lacking STP2 and PUT3 exhibits a severe alkalization defect that nearly phenocopies that of a gdh2‐/‐ strain. Alkalization is dependent on mitochondrial activity and in wild‐type cells occurs as long as the conditions permit respiratory growth. Strikingly, Gdh2 levels decrease and cells transiently extrude glutamate as the environment becomes more alkaline. Together, these processes constitute a rudimentary regulatory system that counters and limits the negative effects associated with ammonia generation. These findings align with Gdh2 being dispensable for virulence, and based on a whole human blood virulence assay, the same is true for C. glabrata and C. auris. Using a transwell co‐culture system, we observed that the growth and proliferation of Lactobacillus crispatus, a common component of the acidic vaginal microenvironment and a potent antagonist of C. albicans, is unaffected by fungal‐induced alkalization. Consequently, although Candida spp. can alkalinize their growth environments, other fungal‐associated processes are more critical in promoting dysbiosis and virulent fungal growth.