Genetic adaptive mechanisms mediating response and tolerance to acetic acid stress in the human pathogen Candida glabrata: role of the CgHaa1-dependent signaling pathway
C. glabrata is a commensal found in the human genitourinary tract but under certain conditions this
harmless colonization evolves to a mucosal infection and, in more serious cases, to disseminated
mycosis. To thrive in the acidic vaginal tract C. glabrata has to cope with the presence of a competing
commensal microbiota known to restrain the overgrowth of pathogens through the production of acetic
and lactic acids, among other interference effects. The persistent emergence of C. glabrata strains
resistant to currently used antifungals demands the implementation of novel therapeutic strategies
based on non-conventional targets. Genes contributing to increase C. glabrata competitiveness in the
vaginal tract by mediating tolerance to the organic acids found therein are a cohort of interesting and
yet unexplored therapeutic targets.
Tolerance mechanisms of C. glabrata to acetic acid at low pH are poorly studied but much knowledge
was gathered in Saccharomyces cerevisiae (Mira et al 2010a; 2010b; 2011; 2010c). In particular,
the central role of the ScHaa1 transcription factor in mediating S. cerevisiae tolerance to acetic acid
stress was demonstrated (Mira et al 2010b; 2011; 2010c). In this work it is shown that CgHaa1, an
orthologue of ScHaa1, controls an acetic acid-responsive system in C. glabrata. The mechanisms by
which the CgHaa1 pathway mediate tolerance to acetic acid in C. glabrata were further dissected,
exploring a transcriptomics approach, being of notice the involvement of this regulatory system in
the control of internal pH and in reducing the internal accumulation of the acid. In the presence of
acetic acid CgHaa1 enhanced adhesion and colonization of reconstituted vaginal human epithelium
by C. glabrata, this correlating with a positive effect of CgHaa1 over the expression of adhesinencoding
genes. The results obtained show similarities, but also remarkable differences, in the way
by which the ScHaa1 and CgHaa1 pathways mediate tolerance to acetic acid in S. cerevisiae and in
C. glabrata, indicating a functional expansion of the network in the later species. The role of the
CgHaa1-pathway in the extreme acetic acid-tolerance exhibited by vaginal C. glabrata isolates will
also be discussed, along with other uncovered mechanistic insights
