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PMID:24355926

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Citation

Gebremariam, T, Liu, M, Luo, G, Bruno, V, Phan, QT, Waring, AJ, Edwards, JE Jr, Filler, SG, Yeaman, MR and Ibrahim, AS (2014) CotH3 mediates fungal invasion of host cells during mucormycosis. J. Clin. Invest. 124:237-50

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.

Links

PubMed PMC3871245 Online version:10.1172/JCI71349

Keywords


Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

RHIO9:COTH2

involved_in

GO:0044652: adhesion of symbiont to host endothelial cell

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

RHIO9:COTH2

involved_in

GO:0044409: entry into host

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

RHIO9:COTH2

enables

GO:0046789: host cell surface receptor binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

RHIO9:COTH3

involved_in

GO:0044652: adhesion of symbiont to host endothelial cell

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

RHIO9:COTH3

involved_in

GO:0044409: entry into host

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

RHIO9:COTH3

enables

GO:0046789: host cell surface receptor binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

BACSU:COTH

GO:0030435: sporulation resulting in formation of a cellular spore

ECO:0000314:

P

Figure 3: These pictures show that this inner spore coat protein H, CotH, acts as a fungal ligand for GRP78.

complete
CACAO 9432

See also

References

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