GRP78 and Integrins Play Different Roles in Host Cell Invasion during Mucormycosis

ABSTRACT Mucormycosis, caused by Rhizopus species, is a life-threatening fungal infection that occurs in patients immunocompromised by diabetic ketoacidosis (DKA), cytotoxic chemotherapy, immunosuppressive therapy, hematologic malignancies, or severe trauma. Inhaled Rhizopus spores cause pulmonary i...

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Autores principales:	Abdullah Alqarihi, Teclegiorgis Gebremariam, Yiyou Gu, Marc Swidergall, Sondus Alkhazraji, Sameh S. M. Soliman, Vincent M. Bruno, John E. Edwards, Scott G. Filler, Priya Uppuluri, Ashraf S. Ibrahim
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	GRP78 integrin β1 Rhizopus mucormycosis cell invasion epithelial cells Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/fc592c0e16344630a9d76814776e0000
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spelling	oai:doaj.org-article:fc592c0e16344630a9d76814776e00002021-11-15T15:56:46ZGRP78 and Integrins Play Different Roles in Host Cell Invasion during Mucormycosis10.1128/mBio.01087-202150-7511https://doaj.org/article/fc592c0e16344630a9d76814776e00002020-06-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01087-20https://doaj.org/toc/2150-7511ABSTRACT Mucormycosis, caused by Rhizopus species, is a life-threatening fungal infection that occurs in patients immunocompromised by diabetic ketoacidosis (DKA), cytotoxic chemotherapy, immunosuppressive therapy, hematologic malignancies, or severe trauma. Inhaled Rhizopus spores cause pulmonary infections in patients with hematologic malignancies, while patients with DKA are much more prone to rhinoorbital/cerebral mucormycosis. Here, we show that Rhizopus delemar interacts with glucose-regulated protein 78 (GRP78) on nasal epithelial cells via its spore coat protein CotH3 to invade and damage the nasal epithelial cells. Expression of the two proteins is significantly enhanced by high glucose, iron, and ketone body levels (hallmark features of DKA), potentially leading to frequently lethal rhinoorbital/cerebral mucormycosis. In contrast, R. delemar CotH7 recognizes integrin β1 as a receptor on alveolar epithelial cells, causing the activation of epidermal growth factor receptor (EGFR) and leading to host cell invasion. Anti-integrin β1 antibodies inhibit R. delemar invasion of alveolar epithelial cells and protect mice from pulmonary mucormycosis. Our results show that R. delemar interacts with different mammalian receptors depending on the host cell type. Susceptibility of patients with DKA primarily to rhinoorbital/cerebral disease can be explained by host factors typically present in DKA and known to upregulate CotH3 and nasal GRP78, thereby trapping the fungal cells within the rhinoorbital milieu, leading to subsequent invasion and damage. Our studies highlight that mucormycosis pathogenesis can potentially be overcome by the development of novel customized therapies targeting niche-specific host receptors or their respective fungal ligands. IMPORTANCE Mucormycosis caused by Rhizopus species is a fungal infection with often fatal prognosis. Inhalation of spores is the major route of entry, with nasal and alveolar epithelial cells among the first cells that encounter the fungi. In patients with hematologic malignancies or those undergoing cytotoxic chemotherapy, Rhizopus causes pulmonary infections. On the other hand, DKA patients predominantly suffer from rhinoorbital/cerebral mucormycosis. The reason for such disparity in disease types by the same fungus is not known. Here, we show that the unique susceptibility of DKA subjects to rhinoorbital/cerebral mucormycosis is likely due to specific interaction between nasal epithelial cell GRP78 and fungal CotH3, the expression of which increases in the presence of host factors present in DKA. In contrast, pulmonary mucormycosis is initiated via interaction of inhaled spores expressing CotH7 with integrin β1 receptor, which activates EGFR to induce fungal invasion of host cells. These results introduce a plausible explanation for disparate disease manifestations in DKA versus those in hematologic malignancy patients and provide a foundation for development of therapeutic interventions against these lethal forms of mucormycosis.Abdullah AlqarihiTeclegiorgis GebremariamYiyou GuMarc SwidergallSondus AlkhazrajiSameh S. M. SolimanVincent M. BrunoJohn E. EdwardsScott G. FillerPriya UppuluriAshraf S. IbrahimAmerican Society for MicrobiologyarticleGRP78integrin β1Rhizopusmucormycosiscell invasionepithelial cellsMicrobiologyQR1-502ENmBio, Vol 11, Iss 3 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	GRP78 integrin β1 Rhizopus mucormycosis cell invasion epithelial cells Microbiology QR1-502
spellingShingle	GRP78 integrin β1 Rhizopus mucormycosis cell invasion epithelial cells Microbiology QR1-502 Abdullah Alqarihi Teclegiorgis Gebremariam Yiyou Gu Marc Swidergall Sondus Alkhazraji Sameh S. M. Soliman Vincent M. Bruno John E. Edwards Scott G. Filler Priya Uppuluri Ashraf S. Ibrahim GRP78 and Integrins Play Different Roles in Host Cell Invasion during Mucormycosis
description	ABSTRACT Mucormycosis, caused by Rhizopus species, is a life-threatening fungal infection that occurs in patients immunocompromised by diabetic ketoacidosis (DKA), cytotoxic chemotherapy, immunosuppressive therapy, hematologic malignancies, or severe trauma. Inhaled Rhizopus spores cause pulmonary infections in patients with hematologic malignancies, while patients with DKA are much more prone to rhinoorbital/cerebral mucormycosis. Here, we show that Rhizopus delemar interacts with glucose-regulated protein 78 (GRP78) on nasal epithelial cells via its spore coat protein CotH3 to invade and damage the nasal epithelial cells. Expression of the two proteins is significantly enhanced by high glucose, iron, and ketone body levels (hallmark features of DKA), potentially leading to frequently lethal rhinoorbital/cerebral mucormycosis. In contrast, R. delemar CotH7 recognizes integrin β1 as a receptor on alveolar epithelial cells, causing the activation of epidermal growth factor receptor (EGFR) and leading to host cell invasion. Anti-integrin β1 antibodies inhibit R. delemar invasion of alveolar epithelial cells and protect mice from pulmonary mucormycosis. Our results show that R. delemar interacts with different mammalian receptors depending on the host cell type. Susceptibility of patients with DKA primarily to rhinoorbital/cerebral disease can be explained by host factors typically present in DKA and known to upregulate CotH3 and nasal GRP78, thereby trapping the fungal cells within the rhinoorbital milieu, leading to subsequent invasion and damage. Our studies highlight that mucormycosis pathogenesis can potentially be overcome by the development of novel customized therapies targeting niche-specific host receptors or their respective fungal ligands. IMPORTANCE Mucormycosis caused by Rhizopus species is a fungal infection with often fatal prognosis. Inhalation of spores is the major route of entry, with nasal and alveolar epithelial cells among the first cells that encounter the fungi. In patients with hematologic malignancies or those undergoing cytotoxic chemotherapy, Rhizopus causes pulmonary infections. On the other hand, DKA patients predominantly suffer from rhinoorbital/cerebral mucormycosis. The reason for such disparity in disease types by the same fungus is not known. Here, we show that the unique susceptibility of DKA subjects to rhinoorbital/cerebral mucormycosis is likely due to specific interaction between nasal epithelial cell GRP78 and fungal CotH3, the expression of which increases in the presence of host factors present in DKA. In contrast, pulmonary mucormycosis is initiated via interaction of inhaled spores expressing CotH7 with integrin β1 receptor, which activates EGFR to induce fungal invasion of host cells. These results introduce a plausible explanation for disparate disease manifestations in DKA versus those in hematologic malignancy patients and provide a foundation for development of therapeutic interventions against these lethal forms of mucormycosis.
format	article
author	Abdullah Alqarihi Teclegiorgis Gebremariam Yiyou Gu Marc Swidergall Sondus Alkhazraji Sameh S. M. Soliman Vincent M. Bruno John E. Edwards Scott G. Filler Priya Uppuluri Ashraf S. Ibrahim
author_facet	Abdullah Alqarihi Teclegiorgis Gebremariam Yiyou Gu Marc Swidergall Sondus Alkhazraji Sameh S. M. Soliman Vincent M. Bruno John E. Edwards Scott G. Filler Priya Uppuluri Ashraf S. Ibrahim
author_sort	Abdullah Alqarihi
title	GRP78 and Integrins Play Different Roles in Host Cell Invasion during Mucormycosis
title_short	GRP78 and Integrins Play Different Roles in Host Cell Invasion during Mucormycosis
title_full	GRP78 and Integrins Play Different Roles in Host Cell Invasion during Mucormycosis
title_fullStr	GRP78 and Integrins Play Different Roles in Host Cell Invasion during Mucormycosis
title_full_unstemmed	GRP78 and Integrins Play Different Roles in Host Cell Invasion during Mucormycosis
title_sort	grp78 and integrins play different roles in host cell invasion during mucormycosis
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/fc592c0e16344630a9d76814776e0000
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_version_	1718427130475315200

GRP78 and Integrins Play Different Roles in Host Cell Invasion during Mucormycosis

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