UMMS Affiliation
Department of Microbiology and Physiological Systems; Gastroenterology Division, Department of Medicine
Publication Date
2019-04-02
Document Type
Article
Disciplines
Amino Acids, Peptides, and Proteins | Computational Biology | Genetic Phenomena | Immunoprophylaxis and Therapy | Microbiology | Viruses
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
Rights and Permissions
Copyright © 2019 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).
DOI of Published Version
10.1073/pnas.1814850116
Source
Proc Natl Acad Sci U S A. 2019 Apr 2;116(14):7043-7052. doi: 10.1073/pnas.1814850116. Epub 2019 Mar 20. Link to article on publisher's site
Journal/Book/Conference Title
Proceedings of the National Academy of Sciences of the United States of America
Related Resources
PubMed ID
30894498
Repository Citation
E X, Meraner P, Lu P, Perreira JM, Aker AM, McDougall WM, Zhuge R, Chan GC, Gerstein RM, Caposio P, Yurochko AD, Brass AL, Kowalik TF. (2019). OR14I1 is a receptor for the human cytomegalovirus pentameric complex and defines viral epithelial cell tropism. Open Access Articles. https://doi.org/10.1073/pnas.1814850116. Retrieved from https://escholarship.umassmed.edu/oapubs/3813
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.
Included in
Amino Acids, Peptides, and Proteins Commons, Computational Biology Commons, Genetic Phenomena Commons, Immunoprophylaxis and Therapy Commons, Microbiology Commons, Viruses Commons