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/GROalpha, CXCL2/GRObeta, CXCL3/GROgamma, 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.
Highlights
VCXCL1 Targets CXCR1 and CXCR2 as an Agonist When Screened against a Panel of the Human Chemokine Receptors— To screen for a possible interaction of the UL146 encoded gene product vCXCL1 with the 18 known human chemokine receptors, vCXCL1 was probed in calcium mobilization assays on a panel of cell lines individually expressing these receptors
For CXCR1 the response was of lower magnitude compared with the response generated by CXCL8, indicating a lower potency for vCXCL1 on this receptor. vCXCL1 was not able to induce a calcium response in any of the 10 other stable L1.2 cell lines expressing CCR1, 3, 4, 5, 6, 7, 8, and 10, CXCR6, and CX3CR1, showing that the effect was mediated through CXCR1 and CXCR2 and not an endogenous receptor in L1.2 cells
These results show that vCXCL1 is able to desensitize the response of CXCL8 through the CXCR1 receptor
Summary
Binding affinities for the CMV UL146 gene product vCXCL1 compared with the human ELR-positive CXC chemokines on CXCR1 and CXCR2 125I-CXCL8 displacement experiments with vCXCL1 and the human ELR-positive CXC chemokines on CHO cells stably transfected with either CXCR1 or CXCR2.
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