The Cytomegalovirus UL146 Gene Product vCXCL1 Targets Both CXCR1 and CXCR2 as an Agonist

Abstract

Large DNA viruses, such as herpesvirus and poxvirus, encode proteins that target and exploit the chemokine system of their host. UL146 and UL147 in the cytomegalovirus (CMV) genome encode the two CXC chemokines vCXCL1 and vCXCL2. In this study, vCXCL1 was probed against a panel of the 18 classified human chemokine receptors. In calcium mobilization assays vCXCL1 acted as an agonist on both CXCR1 and CXCR2 but did not activate or block any of the other 16 chemokine receptors. vCXCL1 was characterized and compared with CXCL1/GRO␣, CXCL2/GRO␤, CXCL3/GRO␥, CXCL5/ENA-78, CXCL6/GCP-2, CXCL7/NAP-2 and CXCL8/IL-8 in competition binding, calcium mobilization, inositol triphosphate turnover, and chemotaxis assays using CXCR1-and CXCR2-expressing Chinese hamster ovary, 300.19, COS7, and L1.2 cells. The affinities of vCXCL1 for the CXCR1 and CXCR2 receptors were 44 and 5.6 nM, respectively, as determined in competition binding against radioactively labeled CXCL8. In calcium mobilization, phosphatidylinositol turnover, and chemotaxis assays, vCXCL1 acted as a highly efficacious activator of both receptors, with a rather low potency for the CXCR1 receptor but comparable with CXCL5 and CXCL7. It is suggested that CMV uses the UL146 gene product expressed in infected endothelial cells to attract neutrophils by activating their CXCR1 and CXCR2 receptors, whereby neutrophils can act as carriers of the virus to uninfected endothelial cells. In that way a lasting pool of CMV-infected endothelial cells could be maintained.

Global Mapping of O-Glycosylation of Varicella Zoster Virus, Human Cytomegalovirus, and Epstein-Barr Virus

“…The secreted RANTES-specific chemokine receptor UL22A (also known as UL21.5) was found heavily glycosylated, as previously reported (68,69). One of the HCMV-en- coded chemokines, vCXCL1, which is thought to attract neutrophils for dissemination, was also found to be O-glycosylated, as recently shown (70,71). Four of HCMV immunoevasins, UL16, US3, US8, and US20, were identified to carry O-glycans (Fig.…”

Cytomegalovirus Expresses the Chemokine Homologue vXCL1 Capable of Attracting XCR1 + CD4 − Dendritic Cells

“…So far, all CMV-encoded chemokines have been classified as either CXC or CC chemokines and have been shown to attract neutrophils (17), monocytes (25), macrophages (63), and CD4 T cells (20). vXCL1 is the first reported CMV-encoded C chemokine that targets XCR1 ϩ CD4 Ϫ DC.…”

“…UL146 and UL147 encode the proteins vCXC-1 and vCXC-2, respectively. Only vCXC-1 has been shown to represent a functional chemokine since it binds to the chemokine receptors CXCR1 and CXCR2 and induces migration of neutrophils to the site of infection (17), a process that has been suggested to facilitate viral dissemination. Whereas one study showed that the UL128 gene product pUL128 blocked migration and induced downregulation of chemokine receptors in monocytes (18), another report demonstrated an opposite effect for pUL128, as it induced migration of peripheral blood mononuclear cells (19), a discrepancy that might be due to N-terminal modifications of the chemokines resulting in different chemotactic behavior.…”

HCMV-Encoded UL128 Enhances TNF-α and IL-6 Expression and Promotes PBMC Proliferation Through the MAPK/ERK PathwayIn Vitro

“…The HCMV UL146 gene produces a viral chemokine (vCXCL-1), which was shown to bind exclusively to CXCR2, and can induce calcium flux and chemotaxis of neutrophils that may contribute to increased viral dissemination and virulence (22). A previous study showed that the HCMV UL128 gene was highly conserved in all clinical strains (23).…”