Mutsuo Yamaya, Yoshitaka Shimotai, Yukimasa Hatachi, Morio Homma and Hidekazu Nishimura
Influenza virus replication and the production of inflammatory cytokines are associated with symptoms, including fever, and exacerbation of bronchial asthma and chronic obstructive pulmonary disease. Proteolytic activation of influenza viruses by serine proteases that are produced by airway epithelial cells is essential for viral entry and replication. Transmembrane protease serine S1 member (TMPRSS) 2, TMPRSS4 and TMPRSS11D have been detected certain cells, including the human alveolar epithelial cell line A549 and the surface epithelial cells of the human nasal mucosa, the trachea, the distal airways, and the lung. Several protease inhibitors, including aprotinin, reduce influenza virus replication. We previously demonstrated the following: (1) TMPRSSs (TMPRSS2, 4, and 11D) are present in primary cultures of human tracheal epithelial cells; (2) serine protease inhibitors, such as camostat and aprotinin, reduce the influenza virus replication and the release of the cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-α into cell supernatants; and (3) camostat reduces the cleavage of an influenza virus precursor protein, HA0, into the subunit HA1. These findings suggest that serine proteases expressed by human tracheal epithelial cells induce the proteolytic activation of influenza viruses and that serine protease inhibitors may reduce viral replication and the resultant production of inflammatory cytokines. Thus, serine protease inhibitors are potential candidates for anti-influenza virus drugs
Here, we review the expression of serine proteases, the role of serine proteases in influenza virus activation, and the effects of serine protease inhibitors. In this review, we aim to introduce the effects of serine proteases and their inhibitors on influenza virus infection of human airway epithelial cells by discussing the findings of previous studies performed by our group and other research groups. Furthermore, the clinical features and virulence of influenza virus infection are reviewed to clarify the association of virus replication and cytokine release with disease severity.