Neutrophils in Respiratory Viral Infection: Immunopathology and Therapeutic Strategies

The respiratory tract is constantly exposed to microbes from the surrounding environment. This mucosal barrier requires precise control and response mechanisms that preserve gas exchange while maintaining barrier integrity. Neutrophils, the most abundant leukocytes, are key to maintaining this homeostasis. Both lung-resident and recruited neutrophils migrate to inflamed areas, where they perform effector functions such as phagocytosis, degranulation, reactive oxygen species production, and neutrophil extracellular trap (NET) formation. These processes are tightly regulated, with immune cells such as alveolar macrophages helping to balance pathogen clearance and inflammation. Emerging evidence indicates that neutrophils contribute to inflammation and tissue damage beyond their antimicrobial roles. Elevated neutrophil levels and activation are associated with disease severity and poor outcomes following respiratory viral infection. In addition, respiratory viruses can hijack neutrophil functions to disrupt immune regulation and promote viral replication. Thus, neutrophil dysregulation has been proposed as a target for reducing acute disease severity and preventing lung injury. However, neutrophils exhibit both protective and pathogenic roles during infection, requiring therapeutic strategies that preserve their host defense while limiting pathological effects. This review summarizes current knowledge of neutrophil biology and their immunopathological roles in respiratory viral infections, focusing on Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), Influenza A virus (IAV), and Respiratory Syncytial Virus (RSV). We also discuss therapeutic approaches targeting neutrophils, including preclinical and clinical studies, highlighting ongoing efforts to modulate neutrophil-driven inflammation.