Neutrophils and Influenza: A Thin Line between Helpful and Harmful

Influenza viruses are one of the most prevalent respiratory pathogens known to humans and pose a significant threat to global public health each year. Annual influenza epidemics are responsible for 3-5 million infections worldwide and approximately 500,000 deaths. Presently, yearly vaccinations represent the most effective means of combating these viruses. In humans, influenza viruses infect respiratory epithelial cells and typically cause localized infections of mild to moderate severity. Neutrophils are the first innate cells to be recruited to the site of the infection and possess a wide range of effector functions to eliminate viruses. Some well-described effector functions include phagocytosis, degranulation, the production of reactive oxygen species (ROS), and the formation of neutrophil extracellular traps (NETs). However, while these mechanisms can promote infection resolution, they can also contribute to the pathology of severe disease. Thus, the role of neutrophils in influenza viral infection is nuanced, and the threshold at which protective functions give way to immunopathology is not well understood. Moreover, notable differences between human and murine neutrophils underscore the need to exercise caution when applying murine findings to human physiology. This review aims to provide an overview of neutrophil characteristics, their classic effector functions, as well as more recently described antibody-mediated effector functions. Finally, we discuss the controversial role these cells play in the context of influenza virus infections and how our knowledge of this cell type can be leveraged in the design of universal influenza virus vaccines.