GRP78 and integrins play different roles in host cell invasion during mucormycosis
PublisherAmerican Society for Microbiology
MetadataShow full item record
AbstractMucormycosis, 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. Copyright 2020 Alqarihi et al.
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85085909085&doi=10.1128%2fmBio.01087-20&partnerID=40&md5=4e60c819620bca5127c80f1bf0e588f4; http://hdl.handle.net/10713/13097
- CotH3 mediates fungal invasion of host cells during mucormycosis.
- Authors: Gebremariam T, Liu M, Luo G, Bruno V, Phan QT, Waring AJ, Edwards JE Jr, Filler SG, Yeaman MR, Ibrahim AS
- Issue date: 2014 Jan
- Anti-CotH3 antibodies protect mice from mucormycosis by prevention of invasion and augmenting opsonophagocytosis.
- Authors: Gebremariam T, Alkhazraji S, Soliman SSM, Gu Y, Jeon HH, Zhang L, French SW, Stevens DA, Edwards JE Jr, Filler SG, Uppuluri P, Ibrahim AS
- Issue date: 2019 Jun
- Inhibition of EGFR Signaling Protects from Mucormycosis.
- Authors: Watkins TN, Gebremariam T, Swidergall M, Shetty AC, Graf KT, Alqarihi A, Alkhazraji S, Alsaadi AI, Edwards VL, Filler SG, Ibrahim AS, Bruno VM
- Issue date: 2018 Aug 14
- The endothelial cell receptor GRP78 is required for mucormycosis pathogenesis in diabetic mice.
- Authors: Liu M, Spellberg B, Phan QT, Fu Y, Fu Y, Lee AS, Edwards JE Jr, Filler SG, Ibrahim AS
- Issue date: 2010 Jun
- Bicarbonate correction of ketoacidosis alters host-pathogen interactions and alleviates mucormycosis.
- Authors: Gebremariam T, Lin L, Liu M, Kontoyiannis DP, French S, Edwards JE Jr, Filler SG, Ibrahim AS
- Issue date: 2016 Jun 1