(160bd) A Technical Review of Respiratory Infection Mathematical Models in the Context of Sex-Specific Outcomes

Differences in immune response between males and females greatly impacts outcomes in Influenza A virus (IAV) infection (H1N1 and H5N1). Female’s increased adaptive immune response during reproductive years affords better overall protection than men against viral infection. However, distinct innate immune responses are thought to be a factor of increased mortality rates in women infected with select influenza viruses, as evidenced in the 2009 H1N1 pandemic and the 2013 H7N9 outbreak [1]. Sex-specific disease outcomes are also apparent with SAR-CoV-2 infection, as men are more vulnerable to severe disease and death than women [2]. Sex hormones have been shown to have large effects on immune response. Importantly, it has been shown treatment with estradiol can reduce the increased inflammation due to IAV and reduce mortality in mice [1]. It is hypothesized that IAV therefore inhibits the effects of estradiol, which leads to increased inflammation during infection [3]. Additional work needs to be done in order to understand the mechanism of how IAV impacts production of estradiol, and the impact this has on the immune system and disease outcomes. The immune system is regulated by the various chemical and biological interactions that comprise the system. We argue that poorly regulated immunity is an emergent, systems-level property resulting from changes in immune regulation. Computational models are a powerful tool for modeling complex, dynamic systems such as the immune system in order to help isolate differently regulated components. First, we will review how mechanisms proposed for estradiol activity effect current models of lung immunity. Based on these results, we will perform a technical review of current mathematical models of lung immune response to respiratory infection to determine which models best replicate sex-specific outcomes based on how estradiol alters immune signaling. After this initial study, we will select the best performing model and then use experimental data from male and female mice infected with pandemic and seasonal flu strains to identify the immunological components (i.e. model parameters) that are differently regulated between the sexes. After completion of this study, we expect to have identified the key immunologic complements effected by estradiol and to have produced a model that can be leveraged to identify the optimal dosing strategy to improve infection outcomes using estradiol or estradiol inhibitors.

References

[1] vom Steeg, L.G., Klein, S.L. Sex and sex steroids impact influenza pathogenesis across the life course. Semin Immunopathol 41, 189–194 (2019). https://doi.org/10.1007/s00281-018-0718-5

[2] Takahashi, Takehiro, and Akiko Iwasaki. Sex differences in immune responses. Science 371, 347-348 (2021). doi: 10.1126/science.abe7199.

[3] Klein SL, Flanagan KL. Sex differences in immune responses. Nat Rev Immunol. 2016 Oct;16(10):626-38. doi: 10.1038/nri.2016.90.