Assessment of a recombinant influenza virus carrying interleukin 7 gene as a platform for novel immunotherapeutic approaches.

Influenza virus remains a major global public health threat due to its high transmissibility, ability to cause severe disease, and pandemic potential. Although vaccination is the main strategy for reducing the burden of influenza, it has notable limitations. Therefore, novel therapeutic and immunomodulatory approaches are urgently needed. Here, using plasmid-driven reverse genetics, we engineered a defective recombinant influenza virus encoding interleukin 7 (Flu:IL-7), to investigate the role of IL-7 in influenza pathogenesis and immunomodulation in a murine model. Our findings demonstrate that Flu:IL-7 is safe and effectively attenuates disease severity caused by a wild-type replicative influenza virus (PR8), improving clinical recovery and reducing disease-associated morbidity. Notably, local expression of IL-7 through the Flu:IL-7 vector at the time of PR8 infection significantly reduced the severity of secondary pneumococcal pneumonia. These protective effects were associated with earlier and more coordinated pulmonary immune response, characterized by enhanced activation and expansion of innate and adaptive immune cells, early formation of iBALT-like aggregates, and reduced tissue damage. Collectively, our findings suggest that transient local IL-7 expression temporally reprograms the pulmonary immune response, promoting early antiviral immunity followed by timely resolution of inflammation. In summary, Flu:IL-7 provides a useful experimental model for investigating the immunomodulatory role of IL-7 during influenza infection. Our findings support transient local IL-7 expression as a promising host-directed strategy to improve disease outcome and reduce influenza-associated complications. These concepts may also be applicable to other diseases in which modulation of the local immune response is desirable, including lung cancer and COVID-19.