In humans, differences in the immune response between males and females greatly influence influenza virus infection outcomes. During the 2009 H1N1 pandemic, females were at greater risk than their male, age-matched counterparts for hospitalization and death by a ratio of nearly 3:2. The innate immune response has been implicated as a factor of these sex differences in influenza pathogenesis, with sex hormones considered an important component of innate immune regulation. Together with our collaborators at the University of Wisconsin, Madison, we have completed experiments on male and female mice infected with CA04 H1N1 influenza infection. The results of these experiments show that the female mice have increased viral production at 36 hours post infection, resulting in early and excessive innate immune activation characterized by the proinflammatory cytokine profiles. Immune cell counts show that alveolar macrophages have increased depletion in female mice, while exfiltrating macrophage cell counts are higher at 3 days post infection in female mice: both observations have been associated with increased disease severity. Finally, histopathology of the lung cells shows very few lesions in the male mice compared to female mice. These lesions are present in the alveolar region of the female mice, but not male, indicating that influenza virus penetrates more deeply in the female lungs. While the experimental data points to certain cytokine/chemokines and immune cells as potential factors influencing severity, mathematical modeling can further contribute to our understanding of increased disease severity in females by identifying sex-specific rates within the immune response to infection that differs between males and females. We are currently developing a mathematical model to identify mechanism(s) responsible for the observed increases in disease severity in the female mice. We will use the results of the modeling to inform future experiments and identify potential target treatment pathways.
