Inhibition of EGFR Signaling Protects from Mucormycosis

ABSTRACT Mucormycosis is a life-threatening, invasive fungal infection that is caused by various species belonging to the order Mucorales. Rhizopus species are the most common cause of the disease, responsible for approximately 70% of all cases of mucormycosis. During pulmonary mucormycosis, inhaled...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Tonya N. Watkins, Teclegiorgis Gebremariam, Marc Swidergall, Amol C. Shetty, Karen T. Graf, Abdullah Alqarihi, Sondus Alkhazraji, Abrar I. Alsaadi, Vonetta L. Edwards, Scott G. Filler, Ashraf S. Ibrahim, Vincent M. Bruno
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	EGFR gefitinib Rhizopus mucormycosis Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/32f7502b0b9043d4bd160585e289d502
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:32f7502b0b9043d4bd160585e289d502
record_format	dspace
spelling	oai:doaj.org-article:32f7502b0b9043d4bd160585e289d5022021-11-15T16:00:14ZInhibition of EGFR Signaling Protects from Mucormycosis10.1128/mBio.01384-182150-7511https://doaj.org/article/32f7502b0b9043d4bd160585e289d5022018-09-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01384-18https://doaj.org/toc/2150-7511ABSTRACT Mucormycosis is a life-threatening, invasive fungal infection that is caused by various species belonging to the order Mucorales. Rhizopus species are the most common cause of the disease, responsible for approximately 70% of all cases of mucormycosis. During pulmonary mucormycosis, inhaled Rhizopus spores must adhere to and invade airway epithelial cells in order to establish infection. The molecular mechanisms that govern this interaction are poorly understood. We performed an unbiased survey of the host transcriptional response during early stages of Rhizopus arrhizus var. delemar (R. delemar) infection in a murine model of pulmonary mucormycosis using transcriptome sequencing (RNA-seq). Network analysis revealed activation of the host’s epidermal growth factor receptor (EGFR) signaling. Consistent with the RNA-seq results, EGFR became phosphorylated upon in vitro infection of human alveolar epithelial cells with several members of the Mucorales, and this phosphorylated, activated form of EGFR colocalized with R. delemar spores. Inhibition of EGFR signaling with cetuximab or gefitinib, specific FDA-approved inhibitors of EGFR, significantly reduced the ability of R. delemar to invade and damage airway epithelial cells. Furthermore, gefitinib treatment significantly prolonged survival of mice with pulmonary mucormycosis, reduced tissue fungal burden, and attenuated the activation of EGFR in response to pulmonary mucormycosis. These results indicate EGFR represents a novel host target to block invasion of alveolar epithelial cells by R. delemar, and inhibition of EGFR signaling provides a novel approach for treating mucormycosis by repurposing an FDA-approved drug. IMPORTANCE Mucormycosis is an increasingly common, highly lethal fungal infection with very limited treatment options. Using a combination of in vivo animal models, transcriptomics, cell biology, and pharmacological approaches, we have demonstrated that Mucorales fungi activate EGFR signaling to induce fungal uptake into airway epithelial cells. Inhibition of EGFR signaling with existing FDA-approved drugs significantly increased survival following R. arrhizus var. delemar infection in mice. This study enhances our understanding of how Mucorales fungi invade host cells during the establishment of pulmonary mucormycosis and provides a proof-of-concept for the repurposing of FDA-approved drugs that target EGFR function.Tonya N. WatkinsTeclegiorgis GebremariamMarc SwidergallAmol C. ShettyKaren T. GrafAbdullah AlqarihiSondus AlkhazrajiAbrar I. AlsaadiVonetta L. EdwardsScott G. FillerAshraf S. IbrahimVincent M. BrunoAmerican Society for MicrobiologyarticleEGFRgefitinibRhizopusmucormycosisMicrobiologyQR1-502ENmBio, Vol 9, Iss 4 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	EGFR gefitinib Rhizopus mucormycosis Microbiology QR1-502
spellingShingle	EGFR gefitinib Rhizopus mucormycosis Microbiology QR1-502 Tonya N. Watkins Teclegiorgis Gebremariam Marc Swidergall Amol C. Shetty Karen T. Graf Abdullah Alqarihi Sondus Alkhazraji Abrar I. Alsaadi Vonetta L. Edwards Scott G. Filler Ashraf S. Ibrahim Vincent M. Bruno Inhibition of EGFR Signaling Protects from Mucormycosis
description	ABSTRACT Mucormycosis is a life-threatening, invasive fungal infection that is caused by various species belonging to the order Mucorales. Rhizopus species are the most common cause of the disease, responsible for approximately 70% of all cases of mucormycosis. During pulmonary mucormycosis, inhaled Rhizopus spores must adhere to and invade airway epithelial cells in order to establish infection. The molecular mechanisms that govern this interaction are poorly understood. We performed an unbiased survey of the host transcriptional response during early stages of Rhizopus arrhizus var. delemar (R. delemar) infection in a murine model of pulmonary mucormycosis using transcriptome sequencing (RNA-seq). Network analysis revealed activation of the host’s epidermal growth factor receptor (EGFR) signaling. Consistent with the RNA-seq results, EGFR became phosphorylated upon in vitro infection of human alveolar epithelial cells with several members of the Mucorales, and this phosphorylated, activated form of EGFR colocalized with R. delemar spores. Inhibition of EGFR signaling with cetuximab or gefitinib, specific FDA-approved inhibitors of EGFR, significantly reduced the ability of R. delemar to invade and damage airway epithelial cells. Furthermore, gefitinib treatment significantly prolonged survival of mice with pulmonary mucormycosis, reduced tissue fungal burden, and attenuated the activation of EGFR in response to pulmonary mucormycosis. These results indicate EGFR represents a novel host target to block invasion of alveolar epithelial cells by R. delemar, and inhibition of EGFR signaling provides a novel approach for treating mucormycosis by repurposing an FDA-approved drug. IMPORTANCE Mucormycosis is an increasingly common, highly lethal fungal infection with very limited treatment options. Using a combination of in vivo animal models, transcriptomics, cell biology, and pharmacological approaches, we have demonstrated that Mucorales fungi activate EGFR signaling to induce fungal uptake into airway epithelial cells. Inhibition of EGFR signaling with existing FDA-approved drugs significantly increased survival following R. arrhizus var. delemar infection in mice. This study enhances our understanding of how Mucorales fungi invade host cells during the establishment of pulmonary mucormycosis and provides a proof-of-concept for the repurposing of FDA-approved drugs that target EGFR function.
format	article
author	Tonya N. Watkins Teclegiorgis Gebremariam Marc Swidergall Amol C. Shetty Karen T. Graf Abdullah Alqarihi Sondus Alkhazraji Abrar I. Alsaadi Vonetta L. Edwards Scott G. Filler Ashraf S. Ibrahim Vincent M. Bruno
author_facet	Tonya N. Watkins Teclegiorgis Gebremariam Marc Swidergall Amol C. Shetty Karen T. Graf Abdullah Alqarihi Sondus Alkhazraji Abrar I. Alsaadi Vonetta L. Edwards Scott G. Filler Ashraf S. Ibrahim Vincent M. Bruno
author_sort	Tonya N. Watkins
title	Inhibition of EGFR Signaling Protects from Mucormycosis
title_short	Inhibition of EGFR Signaling Protects from Mucormycosis
title_full	Inhibition of EGFR Signaling Protects from Mucormycosis
title_fullStr	Inhibition of EGFR Signaling Protects from Mucormycosis
title_full_unstemmed	Inhibition of EGFR Signaling Protects from Mucormycosis
title_sort	inhibition of egfr signaling protects from mucormycosis
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/32f7502b0b9043d4bd160585e289d502
work_keys_str_mv	AT tonyanwatkins inhibitionofegfrsignalingprotectsfrommucormycosis AT teclegiorgisgebremariam inhibitionofegfrsignalingprotectsfrommucormycosis AT marcswidergall inhibitionofegfrsignalingprotectsfrommucormycosis AT amolcshetty inhibitionofegfrsignalingprotectsfrommucormycosis AT karentgraf inhibitionofegfrsignalingprotectsfrommucormycosis AT abdullahalqarihi inhibitionofegfrsignalingprotectsfrommucormycosis AT sondusalkhazraji inhibitionofegfrsignalingprotectsfrommucormycosis AT abrarialsaadi inhibitionofegfrsignalingprotectsfrommucormycosis AT vonettaledwards inhibitionofegfrsignalingprotectsfrommucormycosis AT scottgfiller inhibitionofegfrsignalingprotectsfrommucormycosis AT ashrafsibrahim inhibitionofegfrsignalingprotectsfrommucormycosis AT vincentmbruno inhibitionofegfrsignalingprotectsfrommucormycosis
_version_	1718426957412040704

Inhibition of EGFR Signaling Protects from Mucormycosis

Ejemplares similares