Local immune responses to influenza virus infection in mice with a targeted disruption of perforin gene

Abstract

The role of perforin in the local defense mechanisms against influenza virus infection was investigated. Mice deficient in the perforin gene (perforin −/−) were more susceptible to influenza virus infection than the ordinary wild-type C57BL/6 mice, showing an increased mortality with elevated virus growth and prolonged virus shedding. The lung parenchyma cells of perforin −/− mice showed no cytolytic activities of natural killer cells or virus-specific cytotoxic T lymphocytes in vitro, although the local antibody production system in the respiratory tract functioned well. In perforin −/− mice, the appearance of apoptotic degeneration in virally infected lung cells was delayed. This might cause cellular infiltration, including CD4, CD8, and CD19 positive cells, in the lung, peaking at day 8 after infection and maintaining a high level for a longer period. In the virus-induced local cytokine production, interferon-gamma (IFN-γ) was prominent. The adoptive transfer of immune-competent spleen cells from wild-type C57BL/6 mice achieved a complete protection of perforin −/− mice against lethal challenge infection. These results suggest that perforin plays a crucial role in the host defense system against influenza virus infection, especially in its early stage, by inducing apoptosis of virus-infected cells.