N-cadherin Mediates Endocytosis of Candida albicans by Endothelial Cells

Phan, Quynh T.; Fratti, Rutilio A.; Prasadarao, Nemani V.; Edwards, John E.; Filler, Scott G.

doi:10.1074/jbc.m412592200

Cited by 105 publications

(110 citation statements)

References 43 publications

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“…These results were concordant with our prior findings that adhesion and invasion of R. oryzae to host cells are independent processes mediated by different receptors (15). The independence of adhesion and invasion processes has been also reported for Candida albicans (26). The probable explanation for the adhesion function of CotH proteins when expressed in S. cerevisiae is that although CotH can mediate both adherence and invasion, in R. oryzae, other adhesins likely exist and can compensate for the loss of CotH function.…”

Section: Figuresupporting

confidence: 83%

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CotH3 mediates fungal invasion of host cells during mucormycosis

Gebremariam¹,

Liu²,

Luo³

et al. 2013

J. Clin. Invest.

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212

294

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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.

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Section: Figuresupporting

confidence: 83%

“…We used a modification of our previously described method (15,26). Confluent endothelial cells on a 12-mm-diameter glass coverslip were infected with 10 5 /ml RPMI 1640 medium R. oryzae cells that had pregerminated for 1 hour.…”

Section: Figurementioning

confidence: 99%

CotH3 mediates fungal invasion of host cells during mucormycosis

Gebremariam¹,

Liu²,

Luo³

et al. 2013

J. Clin. Invest.

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212

294

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“…Epithelial cell membrane proteins that bound to C. albicans or S. cerevisiae were isolated and affinity-purified as previously outlined (5,(28)(29)(30). Proteins eluted from the fungi were separated by SDS/PAGE and detected by immunoblotting with antibodies against biotin (clone BN-32; Sigma-Aldrich), EGFR (sc-03; Santa Cruz Biotechnology), and HER2 (clone 3B5; Santa Cruz Biotechnology).…”

Section: Methodsmentioning

confidence: 99%

“…Confocal Microscopy. The accumulation of epithelial cell EGFR, HER2, and Ecadherin around C. albicans hyphae was visualized using a minor modification of our previously described methods (5,29). OKF6/TERT-2 cells were infected with 2 × 10 5 hyphae of the various C. albicans strains.…”

Section: Methodsmentioning

confidence: 99%

EGFR and HER2 receptor kinase signaling mediate epithelial cell invasion by Candida albicans during oropharyngeal infection

Zhu

Phan

Boontheung

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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162

191

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The fungus Candida albicans is the major cause of oropharyngeal candidiasis (OPC). A key feature of this disease is fungal invasion of oral epithelial cells, a process that can occur by active penetration and fungal-induced endocytosis. Two invasins, Als3 and Ssa1, induce epithelial cell endocytosis of C. albicans, in part by binding to E-cadherin. However, inhibition of E-cadherin function only partially reduces C. albicans endocytosis, suggesting that there are additional epithelial cell receptors for this organism. Here, we show that the EGF receptor (EGFR) and HER2 function cooperatively to induce the endocytosis of C. albicans hyphae. EGFR and HER2 interact with C. albicans in an Als3-and Ssa1-dependent manner, and this interaction induces receptor autophosphorylation. Signaling through both EGFR and HER2 is required for maximal epithelial cell endocytosis of C. albicans in vitro. Importantly, oral infection with C. albicans stimulates the phosphorylation of EGFR and HER2 in the oral mucosa of mice, and treatment with a dual EGFR and HER2 kinase inhibitor significantly decreases this phosphorylation and reduces the severity of OPC. These results show the importance of EGFR and HER2 signaling in the pathogenesis of OPC and indicate the feasibility of treating candidal infections by targeting the host cell receptors with which the fungus interacts.

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“…50 New research has found that N-cadherin expressed on the endothelium binds to C. albicans Als3 and Ssa1 in a complex that also contains an intracellular GTP-binding protein, septin-7. 87,88 This binding process induces endothelial cell microfilaments, thereby producing pseudopods that engulf the organism.…”

Section: Endothelial Cellsmentioning

confidence: 99%

Innate immune cell response uponCandida albicansinfection

Qin

Zhang

et al. 2016

Virulence

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Candida albicans is a polymorphic fungus which is the predominant cause of superficial and deep tissue fungal infections. This microorganism has developed efficient strategies to invade the host and evade host defense systems. However, the host immune system will be prepared for defense against the microbe by recognition of receptors, activation of signal transduction pathways and cooperation of immune cells. As a consequence, C. albicans could either be eliminated by immune cells rapidly or disseminate hematogenously, leading to life-threatening systemic infections. The interplay between Candida albicans and the host is complex, requiring recognition of the invaded pathogens, activation of intricate pathways and collaboration of various immune cells. In this review, we will focus on the effects of innate immunity that emphasize the first line protection of host defense against invaded C. albicans including the basis of receptor-mediated recognition and the mechanisms of cell-mediated immunity.

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N-cadherin Mediates Endocytosis of Candida albicans by Endothelial Cells

Cited by 105 publications

References 43 publications

CotH3 mediates fungal invasion of host cells during mucormycosis

CotH3 mediates fungal invasion of host cells during mucormycosis

EGFR and HER2 receptor kinase signaling mediate epithelial cell invasion by Candida albicans during oropharyngeal infection

Innate immune cell response uponCandida albicansinfection

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