Nonrespiratory sites of influenza-associated disease: mechanisms and experimental systems for continued study

The productive replication of human influenza viruses is almost exclusively restricted to cells in the respiratory tract. However, a key aspect of the host response to viral infection is the production of inflammatory cytokines and chemokines that are not similarly tissue restricted. As such, circulating inflammatory mediators, as well as the resulting activated immune cells, can induce damage throughout the body, particularly in individuals with underlying conditions. As a result, more holistic experimental approaches are required to fully understand the pathogenesis and scope of influenza virus-induced disease. This review summarizes what is known about some of the most well-appreciated nonrespiratory tract sites of influenza virus-induced disease, including neurological, cardiovascular, gastrointestinal, muscular and fetal developmental phenotypes. In the context of this discussion, we describe the in vivo experimental systems currently being used to study nonrespiratory symptoms. Finally, we highlight important future questions and potential models that can be used for a more complete understanding of influenza virus-induced disease.