Chemokine (C-X-C motif) ligand 11 is a crucial antiviral modulator that affects viral replication, the IFN-γ response, and T-cell functions during respiratory syncytial virus infection

Respiratory syncytial virus (RSV) is the leading cause of childhood respiratory infections worldwide. However, no vaccine is available for children, and treatment options are limited. Identification of host factors pivotal to viral replication or immune-inflammatory regulation may inform the development of novel therapies, prophylaxes, or diagnoses. The chemokine (C-X-C motif) ligand 11 (CXCL11), which is drastically increased in RSV-infected respiratory tract samples, was previously found via a metatranscriptome screen, suggesting that CXCL11 may play an important role in RSV infection. In this study, we found that the CXCL11 expression level was negatively associated with the clinical disease severity of RSV infection. Using a CRISPR-Cas9-mediated knockout A549 cell line and a knockout mouse model, we investigated the role of CXCL11 in the pathogenesis of RSV. Our study indicated that CXCL11 restricted RSV infection by interfering with its polymerase activity to inhibit the RSV replication process. Additionally, CXCL11 was crucial for optimizing the IFN-γ response. With a knockout mouse model, we confirmed that CXCL11 not only restricted RSV infection in vivo but was also associated with the severity of lung pathology. In addition, we found out that CXCL11 was indispensable for regulating Th1/Th2 balance, and the cytotoxic and antiviral phenotypes of the CD8+ T-cell response during RSV infection. Finally, we observed that supplementation with recombinant CXCL11 significantly improved the clinical outcomes of RSV infection in mice, as evidenced by reduced weight loss, lower viral titers, and attenuated lung inflammation. Overall, our studies suggested that CXCL11 functions in controlling RSV infection.