Activation of the chemokine receptor CCR1 and preferential recruitment of Gαi suppress RSV replication: implications for developing novel RSV treatment strategies

Li, J.; Xue, L.; wang, j. c.; Meng, A.; Qiao, J.; Li, M.; Wang, X.; Meng, L.; Ning, J.; Gao, X.; Li, W.; Ma, C.; Wei, L.

doi:10.1101/2022.03.18.484968

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bioRxiv · 10.1101/2022.03.18.484968

Activation of the chemokine receptor CCR1 and preferential recruitment of Gαi suppress RSV replication: implications for developing novel RSV treatment strategies

Li, J.·Xue, L.·wang, j. c.·Meng, A.·Qiao, J.·Li, M.·Wang, X.·Meng, L.·Ning, J.·Gao, X.·Li, W.·Ma, C.·Wei, L.

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Abstract

Respiratory syncytial virus (RSV) is a major pathogen that can cause acute respiratory infectious diseases of the upper and lower respiratory tract, especially in children, elderly individuals and immunocompromised people. Generally, following viral infection, respiratory epithelial cells secrete cytokines and chemokines to recruit immune cells and initiate innate and/or adaptive immune responses. However, whether chemokines affect viral replication in non-immune cells is rarely clear. In this study, we detect that chemokine CCL5 was highly expressed, while expression of its receptor, CCR1, was downregulated in respiratory epithelial cells after RSV infection. When we overexpressed CCR1 on respiratory epithelial cells in vivo/in vitro, viral load was significantly suppressed, which can be restored by the neutralizing antibody for CCR1. Interestingly, the antiviral effect of CCR1 was not related to type I interferon (IFN-I), apoptosis induction or viral adhesion or entry inhibition; in contrast, it was related to the preferential recruitment and activation of adaptor Gi, which promoted inositol 1,4,5-triphosphate receptor type 3 (ITPR3) expression, leading to inhibited STAT3 phosphorylation, explicitly, phosphorylated (p)-STAT3 was verified to be among the important factors regulating the activity of HSP90, which has been previously reported to be a chaperone of RSV RNA polymerase. In summary, we are the first to reveal that CCR1 on the surface of non-immune cells regulates RSV replication through a previously unknown mechanism that does not involve IFN-I induction.

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Li, J., Xue, L., wang, j. c., Meng, A., Qiao, J., Li, M., Wang, X., Meng, L., Ning, J., Gao, X., Li, W., Ma, C., Wei, L.. 2022-03-19. Activation of the chemokine receptor CCR1 and preferential recruitment of Gαi suppress RSV replication: implications for developing novel RSV treatment strategies. https://doi.org/10.1101/2022.03.18.484968

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