CotH3 mediates fungal invasion of host cells during mucormycosis
Teclegiorgis Gebremariam, … , Michael R. Yeaman, Ashraf S. Ibrahim
Teclegiorgis Gebremariam, … , Michael R. Yeaman, Ashraf S. Ibrahim
Published December 20, 2013
Citation Information: J Clin Invest. 2014;124(1):237-250. https://doi.org/10.1172/JCI71349.
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Research Article

CotH3 mediates fungal invasion of host cells during mucormycosis

Abstract

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.

Authors

Teclegiorgis Gebremariam, Mingfu Liu, Guanpingsheng Luo, Vincent Bruno, Quynh T. Phan, Alan J. Waring, John E. Edwards Jr., Scott G. Filler, Michael R. Yeaman, Ashraf S. Ibrahim

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Figure 6

Inhibition of CotH2 and CotH3 expression decreases the ability of R. oryzae to invade and damage endothelial cells and GRP78-overexpressing CHO cells.

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Inhibition of CotH2 and CotH3 expression decreases the ability of R. ory...
(A and B) RNAi-transformed R. oryzae germlings caused less invasion (A) and damage (B) to endothelial cells compared with empty plasmid–transformed R. oryzae. (C) RNAi-transformed R. oryzae caused equivalent damage to GRP78-overexpressing versus parent CHO cells. Conversely, wild-type or empty plasmid–transformed R. oryzae germlings caused significantly more damage to GRP78-overexpressing cells. *P < 0.005 vs. empty plasmid, **P < 0.01 vs. wild-type and empty plasmid, ‡P < 0.01 vs. parent cells, Wilcoxon rank-sum test. n = 6 slides/group (A) or 9 wells/group (B) from 3 independent experiments. Data are median ± interquartile range.