Open AccessAn essential role for phosphatidylinositol 3‐kinase in the inhibition of phagosomal maturation, intracellular survival and virulence in C andida glabrata
Author(s) -
Rai Maruti Nandan,
Sharma Vandana,
Balusu Sriram,
Kaur Rupinder
Publication year - 2015
Publication title -
cellular microbiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.542
H-Index - 138
eISSN - 1462-5822
pISSN - 1462-5814
DOI - 10.1111/cmi.12364
Subject(s) - biology , autophagy , microbiology and biotechnology , candida glabrata , phosphatidylinositol , pi3k/akt/mtor pathway , saccharomyces cerevisiae , intracellular parasite , phagolysosome , virulence , genetic screen , intracellular , phagosome , mutant , kinase , signal transduction , gene , biochemistry , candida albicans , apoptosis
Summary The yeast class III phosphoinositide 3‐kinase ( PI3K ) that catalyses production of the lipid signalling molecule, phosphatidylinositol‐3‐phosphate, is primarily implicated in vesicle‐mediated transport and autophagy. In this study, we identified, through a genetic screen, the C andida glabrata CgVPS15 gene, an orthologue of the S accharomyces cerevisiae PI3K regulatory subunit‐encoding open reading frame (ORF) to be required for impairment of phagosomal maturation in human macrophages. We also disrupted catalytic subunit of the C . glabrata PI3K complex, CgVps 34, and found it to be pivotal to arrest mature phagolysosome biogenesis. Further, deletion of either CgVPS 15 or CgVPS 34 rendered C . glabrata cells hyperadherent to epithelial cells and susceptible to the antimicrobial arsenal of primary murine and cultured human macrophages and diverse stresses. Despite no growth retardation at 37°C, C gvps15 Δ and C gvps34 Δ mutants were severely virulence attenuated in mice. We demonstrate that trafficking and/or processing of the vacuolar lumenal hydrolase, carboxypeptidase Y , and the major adhesin, E pa1, rely on PI3K regulatory mechanisms in C . glabrata . By disrupting autophagy‐related PI3K complex genes, we show that C . glabrata PI3K ‐impeded phagolysosomal acidification is primarily owing to its role in cellular trafficking events. Altogether, our findings underscore the essentiality of PI3K signalling in modulation of host immune response, intracellular survival and virulence in C . glabrata .