CotH3 mediates fungal invasion of host cells during mucormycosis

被引:181
作者
Gebremariam, Teclegiorgis [1 ,2 ]
Liu, Mingfu [1 ,2 ]
Luo, Guanpingsheng [1 ,2 ]
Bruno, Vincent [3 ]
Phan, Quynh T. [1 ,2 ]
Waring, Alan J. [4 ,5 ]
Edwards, John E., Jr. [1 ,2 ,5 ]
Filler, Scott G. [1 ,2 ,5 ]
Yeaman, Michael R. [1 ,2 ,4 ,5 ]
Ibrahim, Ashraf S. [1 ,2 ,5 ]
机构
[1] Harbor UCLA Med Ctr, Div Infect Dis, Torrance, CA 90502 USA
[2] Harbor UCLA Med Ctr, St Johns Cardiovasc Res Ctr, Los Angeles Biomed Res Inst, Torrance, CA 90502 USA
[3] Univ Maryland, Sch Med, Dept Microbiol & Immunol, Inst Genome Sci, Baltimore, MD 21201 USA
[4] Harbor UCLA Med Ctr, Div Mol Med, Torrance, CA 90502 USA
[5] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA
关键词
LIPOSOMAL AMPHOTERICIN-B; RHIZOPUS-ORYZAE; ENDOTHELIAL-CELLS; CANDIDA-ALBICANS; IMPROVES SURVIVAL; PROTEIN; TRANSFORMATION; SUSCEPTIBILITY; PATHOGENESIS; ZYGOMYCOSIS;
D O I
10.1172/JCI71349
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Angioinvasion is a hallmark of mucormycosis. Previously, we identified endothelial cell glucose-regulated protein 78 (GRP78) as a receptor for Mucorales that mediates host cell invasion. Here we determined that spore coat protein homologs (CotH) of Mucorales act as fungal ligands for GRP78. CotH proteins were widely present in Mucorales and absent from noninvasive pathogens. Heterologous expression of CotH3 and CotH2 in Saccharomyces cerevisiae conferred the ability to invade host cells via binding to GRP78. Homology modeling and computational docking studies indicated structurally compatible interactions between GRP78 and both CotH3 and CotH2. A mutant of Rhizopus oryzae, the most common cause of mucormycosis, with reduced CotH expression was impaired for invading and damaging endothelial cells and CHO cells overexpressing GRP78. This strain also exhibited reduced virulence in a diabetic ketoacidotic (DKA) mouse model of mucormycosis. Treatment with anti-CotH Abs abolished the ability of R. oryzae to invade host cells and protected DKA mice from mucormycosis. The presence of CotH in Mucorales explained the specific susceptibility of DKA patients, who have increased GRP78 levels, to mucormycosis. Together, these data indicate that CotH3 and CotH2 function as invasins that interact with host cell GRP78 to mediate pathogenic host-cell interactions and identify CotH as a promising therapeutic target for mucormycosis.
引用
收藏
页码:237 / 250
页数:14
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