IFN-λ4 Exhibits Differential Induction and Antiviral Activity in RSV and HMPV Infections

Interferons (IFNs) are essential mediators of the innate immune response to viral infections. Among the type III IFNs, the role of IFN-λ4 in respiratory viral infections remains largely understudied. Respiratory syncytial virus (RSV) and human metapneumovirus (HMPV) are clinically significant pneumoviruses that elicit divergent IFN responses in epithelial cells. Here, we investigate the virus-specific induction and antiviral activity of IFN-λ4 by HMPV and RSV infections. We demonstrate that RSV induces a limited expression of IFN-λ4, which is regulated by the expression of the NS1 protein. Furthermore, RSV and HMPV rely primarily on RIG-I for IFN-λ4 induction. Finally, we show that IFN-λ4 exerts antiviral activity against both viruses, with RSV displaying greater sensitivity. These findings highlight the antiviral role of IFN-λ4 to clinically relevant respiratory viruses.