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

E. Xiaofei, Paul Meraner, Ping Lu, Jill M. Perreira, Aaron M. Aker, William M. McDougall, Ronghua Zhuge, Gary C. Chan, Rachel M. Gerstein, Patrizia Caposio, Andrew D. Yurochko, Abraham L. Brass, Timothy F. Kowalik

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)7043-7052
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number14
DOIs
StatePublished - Apr 2 2019

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Tropism
Epithelial Cells
Cytomegalovirus Infections
Cytomegalovirus
Glycoproteins
Cyclic AMP-Dependent Protein Kinases
Clustered Regularly Interspaced Short Palindromic Repeats
Odorant Receptors
Active Immunotherapy
Adenylate Kinase
cytomegalovirus receptor
Virus Diseases
Endocytosis
Adenylyl Cyclases
Antiviral Agents
Membrane Proteins
Genome
Peptides
Infection

Keywords

  • CRISPR screen
  • Human cytomegalovirus
  • OR14I1
  • Pentameric glycoprotein complex
  • Virus receptor

ASJC Scopus subject areas

  • General

Cite this

OR14I1 is a receptor for the human cytomegalovirus pentameric complex and defines viral epithelial cell tropism. / Xiaofei, E.; Meraner, Paul; Lu, Ping; Perreira, Jill M.; Aker, Aaron M.; McDougall, William M.; Zhuge, Ronghua; Chan, Gary C.; Gerstein, Rachel M.; Caposio, Patrizia; Yurochko, Andrew D.; Brass, Abraham L.; Kowalik, Timothy F.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, No. 14, 02.04.2019, p. 7043-7052.

Research output: Contribution to journalArticle

Xiaofei, E, 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', Proceedings of the National Academy of Sciences of the United States of America, vol. 116, no. 14, pp. 7043-7052. https://doi.org/10.1073/pnas.1814850116
Xiaofei, E. ; Meraner, Paul ; Lu, Ping ; Perreira, Jill M. ; Aker, Aaron M. ; McDougall, William M. ; Zhuge, Ronghua ; Chan, Gary C. ; Gerstein, Rachel M. ; Caposio, Patrizia ; Yurochko, Andrew D. ; Brass, Abraham L. ; Kowalik, Timothy F. / OR14I1 is a receptor for the human cytomegalovirus pentameric complex and defines viral epithelial cell tropism. In: Proceedings of the National Academy of Sciences of the United States of America. 2019 ; Vol. 116, No. 14. pp. 7043-7052.
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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.",
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