Role and mechanism of phosphatidylinositol-specific phospholipase C in survival and virulence of Cryptococcus neoformans |
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Authors: | Chayakulkeeree Methee Sorrell Tania C Siafakas A Rosemary Wilson Christabel F Pantarat Namfon Gerik Kimberly J Boadle Ross Djordjevic Julianne T |
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Affiliation: | Centre for Infectious Diseases and Microbiology, ICPMR and Westmead Millennium Institute, University of Sydney at Westmead Hospital, NSW, 2145, Australia.; Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand.; Centre for Clinical Research Excellence –Infection and Bioethics in Haematological Malignancies, ICPMR and Westmead Millennium Institute, University of Sydney at Westmead Hospital, NSW, 2145, Australia.; Department of Biochemistry and Molecular Biology, Saint Louis University Medical School, MO, 63104, USA.; The Electron Microscope Laboratory, ICPMR and Westmead Millennium Institute, University of Sydney at Westmead Hospital, NSW, 2145, Australia. |
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Abstract: | Phospholipase B1 (Plb1) is secreted after release from its glycosylphosphatidylinositol anchor and is implicated in initiation and dissemination of infection of the pathogenic fungus, Cryptococcus neoformans . To investigate the role of phosphatidylinositol-specific phospholipase C (PI-PLC) in Plb1 secretion, we identified two putative PI-PLC-encoding genes in C. neoformans var. grubii ( PLC1 and PLC2 ), and created Δ plc1 and Δ plc2 deletion mutants. In Δ plc1 , which expressed less PI-PLC activity than wild type (WT), three major cryptococcal virulence traits, Plb1 secretion, melanin production and growth at host temperature (37°C) were abolished and absence of Plb1 secretion coincided with Plb1 accumulation in plasma membranes. In addition, Δ plc1 cell walls were defective, as indicated by cell clumping and irregular morphology, slower growth and an inability to activate mitogen-activated protein kinase (MAPK) in the presence of cell wall-perturbing agents. In contrast to Δ plc2 , which was as virulent as WT, Δ plc1 was avirulent in mice and exhibited attenuated killing of Caenorhabditis elegans at 25°C, demonstrating that mechanism(s) independent of the 37°C growth defect contribute to the virulence composite. We conclude that Plc1 is a central regulator of cryptococcal virulence, acting through the protein kinase C/MAPK pathway, that it regulates release of Plb1 from the plasma membrane and is a candidate antifungal drug target. |
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