(296e) Sex-Specific Immunoregulation: Computational Modeling Approaches to Determine Why Biological Females May Experience Greater Inflammation during Influenza Infection

In humans, biological males and females often experience different outcomes during respiratory infections. Here, we are referring to differences in biological sex (XX and XY) and not gender, which includes behaviors and activities that are determined by society or culture in humans. During the 2009 H1N1 influenza pandemic, adult females were at greater risk than their male, age-matched counterparts for hospitalization and death. Many factors may determine sex-specific outcomes, but there is considerable evidence that sex-specific immune regulation is a key driver of enhanced disease pathology. Severe influenza infections are characterized with aggressive inflammatory responses, and studies show that male and female inflammatory responses differ when infected with a common virus. Yet, it remains unknown how the inflammatory differences emerge. In complex systems, a change in a single component’s behavior impacts the temporal response of other system components. Computational modeling is a powerful tool for determining how changes in the behavior of immune system components lead to changes in the overall system response, and computational modeling can consider multiple hypotheses on how sex-specific immune responses emerge. Our research team develops knowledge-based, mechanistic models of the lung immune system and then employs state-of-the-art optimization and Bayesian inference approaches to rigorously determine how the lung immune system is differently regulated between cohorts. These models can be constructed to consider several factors impacting sex-specific regulation simultaneously, including the effects of hormones and sex chromosome dependent gene regulation. Here, we will discuss our most recent effort where we constructed a computational model of the mouse lung innate immune system and used computational models to determine how the immune system is differently regulated in male and female mice infected with a pandemic H1N1 virus. Our results suggest that not only do the rates of key immune processes, particularly those associated with interferon induction, have to be different between males and females, but that the effectiveness of therapeutic intervention using anti-inflammatory compounds is also sex-specific. The model is now being expanded to include additional immune components and we are currently developing strategies for incorporating hormone regulation.