Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01605;
Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01605.
Proc Natl Acad Sci U S A. 2019 Apr 2;116(14):7043-7052. doi: 10.1073/pnas.1814850116. Epub 2019 Mar 20.
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.
人巨细胞病毒 (HCMV) 五聚体糖蛋白复合物 (PC)，gH-gL-UL128-UL130-UL131A，是病毒感染临床相关细胞类型所必需的，包括上皮细胞，这对于宿主间传播和疾病很重要。我们对不同类型的细胞平行进行了全基因组 CRISPR/Cas9 筛选，以鉴定特定于 HCMV 感染上皮细胞的宿主基因。这项工作鉴定了一个多穿膜蛋白 OR14I1，作为 HCMV 感染的受体。该嗅觉受体家族成员是 HCMV 附着、进入和感染上皮细胞所必需的，并且依赖于病毒 PC 的存在。OR14I1 是 AKT 激活所必需的，并介导 HCMV 的内吞进入。我们进一步发现，上皮细胞中的 HCMV 感染被合成的 OR14I1 肽和环腺苷酸酶和蛋白激酶 A (PKA) 信号抑制剂所阻断。鉴定 OR14I1 为与上皮嗜性相关的 PC 依赖性 HCMV 宿主受体，以及环腺苷酸酶/蛋白激酶 A (PKA)/AKT 介导的信号通路在 HCMV 感染中的作用，揭示了疫苗和抗病毒治疗开发的以前未被认识的靶点。
