4.7 Article

Repurposing Axl Kinase Inhibitors for the Treatment of Respiratory Syncytial Virus Infection

Journal

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
Volume 67, Issue 3, Pages -

Publisher

AMER SOC MICROBIOLOGY
DOI: 10.1128/aac.01487-22

Keywords

Axl; RSV; IFN; antiviral; kinase inhibitor; interferons

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RSV infection is a common pulmonary infection in infants and the elderly, but no specific therapeutics are available. In this study, Axl kinase inhibitors were found to reduce RSV infection and promote the expression of antiviral genes.
Respiratory syncytial virus (RSV) infection persists as a common pathogen of pulmonary infection in infants and in the elderly with high morbidity and mortality. However, no specific therapeutics are available. Axl, a member of the TAM (Tyro3, Axl, and Mertk) family receptor kinases, is a pleiotropic inhibitor of the innate immune response and functions as a negative regulator of interferon pathway activation. In this report, we investigated Axl inhibitors for their effects against RSV infection. Axl inhibition with kinase inhibitors, including BMS-777607, R428, and TP-0903, or Axl ablation resulted in a significant reduction of RSV infection in cell-based assays. In an animal model of pulmonary RSV infection, treatment with BMS-777607, R428, or TP-0903 ameliorated pulmonary pathology with a significant reduction of RSV titers in the lung tissues and, consequently, decreased the expression of proinflammatory genes. The host promotes ISG expression for the antiviral response and for viral clearance. We found that Axl inhibition led to more robust IFN-beta expression and antiviral gene induction. Thus, the results of this study imply that Axl kinase inhibitors may possess a broad spectrum of antiviral effects by promoting ISG expression. Respiratory syncytial virus (RSV) infection persists as a common pathogen of pulmonary infection in infants and in the elderly with high morbidity and mortality. However, no specific therapeutics are available.

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