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Proc Natl Acad Sci U S A. 2019 Apr 2;116(14):7043-7052. doi: 10.1073/pnas.1814850116. Epub 2019 Mar 20.

OR14I1 is a receptor for the human cytomegalovirus pentameric complex and defines viral epithelial cell tropism.

Author information

1
Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01605; xiaofei.e@umassmed.edu timothy.kowalik@umassmed.edu.
2
Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01605.
3
Department of Microbiology and Immunology, State University of New York Upstate Medical University, Syracuse, NY 13210.
4
Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97006.
5
Department of Microbiology and Immunology, Center for Molecular & Tumor Virology, Louisiana State University Health Sciences Center, Shreveport, LA 71106.
6
Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, LA 71106.
7
Center for Excellence in Arthritis and Rheumatology, Louisiana State University Health Sciences Center, Shreveport, LA 71106.
8
Gastroenterology Division, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605.
9
Peak Gastroenterology Associates, Colorado Springs, CO 80907.

Abstract

A human cytomegalovirus (HCMV) pentameric glycoprotein complex (PC), gH-gL-UL128-UL130-UL131A, is necessary for viral infection of clinically relevant cell types, including epithelial cells, which are important for interhost transmission and disease. We performed genome-wide CRISPR/Cas9 screens of different cell types in parallel to identify host genes specifically required for HCMV infection of epithelial cells. This effort identified a multipass membrane protein, OR14I1, as a receptor for HCMV infection. This olfactory receptor family member is required for HCMV attachment, entry, and infection of epithelial cells and is dependent on the presence of viral PC. OR14I1 is required for AKT activation and mediates endocytosis entry of HCMV. We further found that HCMV infection of epithelial cells is blocked by a synthetic OR14I1 peptide and inhibitors of adenylate cyclase and protein kinase A (PKA) signaling. Identification of OR14I1 as a PC-dependent HCMV host receptor associated with epithelial tropism and the role of the adenylate cyclase/PKA/AKT-mediated signaling pathway in HCMV infection reveal previously unappreciated targets for the development of vaccines and antiviral therapies.

KEYWORDS:

CRISPR screen; OR14I1; human cytomegalovirus; pentameric glycoprotein complex; virus receptor

PMID:
30894498
PMCID:
PMC6452726
DOI:
10.1073/pnas.1814850116
[Indexed for MEDLINE]
Free PMC Article

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