Diverse mechanisms control amino acid-dependent environmental alkalization byCandida albicans

Abstract

AbstractCandida albicanshas the remarkable capacity to neutralize acidic growth environments by releasing ammonia derived from the catabolism of amino acids. The molecular components and mechanisms controlling this capacity remain poorly understood. Here, we present an integrative model with the cytosolic NAD+-dependent glutamate dehydrogenase (Gdh2) as the principal component. We show that the alkalization defect of a strain lacking the SPS-sensor regulated transcription factorSTP2is due to the inability to fully derepressGDH2and the two proline catabolic enzymes,PUT1andPUT2. Notably, the Stp2-dependent regulation ofPUT1andPUT2occurs independent of Put3, the proline-dependent activator. Accordingly, astp2-/– put3-/-strain is unable to derepress the expression of these enzymes resulting in a severe alkalization defect that nearly phenocopies the abrogated alkalization of agdh2-/-strain. In wildtype cells, alkalization is tightly dependent on mitochondrial activity and occurs as long as conditions permit respiratory growth. As alkalization proceeds, Gdh2 levels decrease and glutamate is transiently extruded from cells. Together these two processes constitute a rudimentary regulatory system enabling cells to prevent the rapid intracellular build-up of ammonia. Similar toC. albicans, Gdh2-dependent alkalization is dispensable forC. glabrataandC. aurisvirulence as assessed using a whole-blood infection model. Intriguingly, fungal-dependent alkalization does not influence the growth or proliferation ofLactobacillus crispatus, a potent antagonist ofC. albicansthat normally resides in the acidic vaginal microenvironment. Our data suggest that it is time to reconsider the idea that pH modulation driven by pathogenic fungi plays a crucial role in shaping the architecture and dynamics of (poly)microbial communities. Other factors are likely to be more critical in contributing to dysbiosis and that favor virulent growth.