Role and mechanism of phosphatidylinositol-specific phospholipase C in survival and virulence of Cryptococcus neoformans

被引:52
作者
Chayakulkeeree, Methee [1 ,2 ,3 ]
Sorrel, Tania C. [1 ,2 ,4 ]
Siafakas, A. Rosemary [1 ,2 ]
Wilson, Christabel F. [1 ,2 ]
Pantarat, Namfon [1 ,2 ]
Gerik, Kimberly J. [5 ]
Boadle, Ross [2 ,6 ]
Djordievic, Julianne T. [1 ,2 ]
机构
[1] Univ Sydney, Westmead Hosp, Ctr Infect Dis & Microbiol, ICPMR, Sydney, NSW 2145, Australia
[2] Univ Sydney, Westmead Hosp, Westmead Millennium Inst, Sydney, NSW 2145, Australia
[3] Mahidol Univ, Siriraj Hosp, Fac Med, Dept Med, Bangkok 10700, Thailand
[4] Univ Sydney, Westmead Hosp, Ctr Clin Res Excellence Infect & Bioeth Haematol, ICPMR, Sydney, NSW 2145, Australia
[5] St Louis Univ, Sch Med, Dept Biochem & Mol Biol, St Louis, MO 63104 USA
[6] Univ Sydney, Westmead Hosp, Electron Microscope Lab, ICPMR, Sydney, NSW 2145, Australia
基金
澳大利亚国家健康与医学研究理事会;
关键词
D O I
10.1111/j.1365-2958.2008.06310.x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 Delta plc1 and Delta plc2 deletion mutants. In Delta 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 degrees C) were abolished and absence of Plb1 secretion coincided with Plb1 accumulation in plasma membranes. In addition, Delta 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 Delta plc2, which was as virulent as WT, Delta plc1 was avirulent in mice and exhibited attenuated killing of Caenorhabditis elegans at 25 degrees C, demonstrating that mechanism(s) independent of the 37 degrees 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.
引用
收藏
页码:809 / 826
页数:18
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