Candida Infection Biology – fungal armoury, battlefields ... - FINSysB

Candida albicans alters extracellular pH under
host-relevant conditions of carbon starvation
Slavena Vylkova, Heather Danhof, and Michael C. Lorenz
Dept. of Microbiology and Molecular Genetics, The University of Texas Health Science
Center, 6431 Fannin St., Houston, TX 77030, USA
Phagocytosis by immune cells, such as macrophages, induces a remarkable
change in transcription and physiology in Candida albicans, with ~10% of the
genome affected. A primary aspect of this response is metabolic shift reflecting
deprivation for carbon, and this response is required for full virulence. We developed
an in vitro system to mimic this response, using media that is glucose-poor and
amino acid-rich; surprisingly, in these conditions, we observed a striking change in
the media pH when C. albicans was grown at an initial pH of 4. Over 12-24 hours,
the pH rose to 7-7.5, and this alkalinization was associated with the induction of
hyphal growth – a key virulence trait in this species. This extracellular pH change
was not dependent on factors previously known to regulate pH responses, such as
RIM101 and MNL1. Using a combination of genetic and genomic screens, we have
linked this process to amino acid catabolism: mutation of genes required for amino
acid permease function and breakdown of amino acids as a carbon source are
impaired in pH changes. Transcript profiles confirm that this pH alteration is the
result of a metabolic change to the use of amino acids as a carbon source, similar
to the profile of phagocytosed cells. Alkalinizing cultures release measurable
quantities of ammonia, a strong base, and we propose that catabolism of amino
acids as a carbon source renders the amine group in excess, and this is excreted
to change the pH. This occurs in conditions that mimic those our data suggest exist
after phagocytosis, and we are now examining the intracellular fate of ingested C.
albicans cells. Published reports are contradictory regarding this fate, but the weight
of evidence indicates intracellular trafficking is aberrant. We propose that C.
albicans alters phagolysosomal pH to induce hyphal growth and impair the
fungicidal effects of the immune cell.
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