Identification of Candida glabrata Genes Involved in pH Modulation and Modification of the Phagosomal Environment in Macrophages
Year: 2014
Type: article
Abstract: Candida glabrata currently ranks as the second most frequent cause of invasive candidiasis. Our previous work has shown that C. glabrata is adapted to intracellular survival in macrophages and replicates within non-acidified late endosomal-stage phagosomes. In contrast, heat killed yeasts are found in acidified matured phagosomes. In the present study, we aimed at elucidating the processes leading to inhibition of phagosome acidification and maturation. We show that phagosomes containing viable C. glabrata cells do not fuse with pre-labeled lysosomes and possess low phagosomal hydrolase activity. Inhibition of acidification occurs independent of macrophage type (human/murine), differentiation (M1-/M2-type) or activation status (vitamin D3 stimulation). We observed no differential activation of macrophage MAPK or NFκB signaling cascades downstream of pattern recognition receptors after internalization of viable compared to heat killed yeasts, but Syk activation decayed faster in macrophages containing viable yeasts. Thus, delivery of viable yeasts to non-matured phagosomes is likely not triggered by initial recognition events via MAPK or NFκB signaling, but Syk activation may be involved. Although V-ATPase is abundant in C. glabrata phagosomes, the influence of this proton pump on intracellular survival is low since blocking V-ATPase activity with bafilomycin A1 has no influence on fungal viability. Active pH modulation is one possible fungal strategy to change phagosome pH. In fact, C. glabrata is able to alkalinize its extracellular environment, when growing on amino acids as the sole carbon source in vitro. By screening a C. glabrata mutant library we identified genes important for environmental alkalinization that were further tested for their impact on phagosome pH. We found that the lack of fungal mannosyltransferases resulted in severely reduced alkalinization in vitro and in the delivery of C. glabrata to acidified phagosomes. Therefore, protein mannosylation may play a key role in alterations of phagosomal properties caused by C. glabrata.
Source: PLoS ONE
Institutions: Leibniz-Institut für Naturstoff-Forschung und Infektionsbiologie e. V. - Hans-Knöll-Institut (HKI), Jena University Hospital, Center for Sepsis Control and Care, Max Perutz Labs, Medical University of Vienna, University of Exeter, Massachusetts General Hospital, Research Center Borstel - Leibniz Lung Center, University of Bonn, Friedrich Schiller University Jena
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,382
Awards: G1003325921, G1817996845, G241908708, G2583166360, Wellcome Strategic Award for Medical Mycology and Fungal Immunology, G2915506405, Modelling the transcriptional proteomic and metabolic redox regulation in Saccharomyces cerevisiae and Candida glabrata, G3541515630, G3755779560, Microevolution of pathogenic yeasts during interactions with the host immune system, Combinatorial Responses of Fungal Pathogens To Their Human Hosts: an Integrative Systems Biology Approach, Wellcome Strategic Award for Medical Mycology and Fungal Immunology, G5270130611, G5570099221, G5611669561, G6644416810, G6956055535, G7268656538, G7824612818, G8528235250
OpenAlex ID: W2080201761