Predictive Modeling of Estradiol Effects and Sex Differences on Immunopathology during Influenza Infection

PROJECT SUMMARY Biologic males and females often experience different outcomes during influenza infection. Sex hormones can mediate the severity of an infection by altering innate immune responses and are one factor influencing sex- dependent differences in infection outcomes. It has also been shown that hormones can impact virus replication in human respiratory cells in a sex-specific manner. However, a systematic understanding of the mechanisms linking hormone levels and biological sex to immunity, virus replication, and disease outcomes is lacking. This research program will leverage predictive, mechanism-based mathematical modeling and network perturbation algorithms to identify the mechanisms by which estradiol (E2), a major sex hormone, regulates the host response during influenza virus infection. And as hormones effect biological males and females differently, we will determine how the mechanisms linking hormone levels and host responses may differ between the sexes. In Aim 1, we will identify the lung host responses that are regulated by estradiol in male and female, influenza- infected mice. Detailed, temporal immunologic and transcriptomic data will be collected, the gene expression data analyzed to identify potential E2-regulated pathways, and dynamical mathematical modeling applied to the immunologic data to identify the immune mechanisms that are affected by hormone treatment. In Aim 2, human respiratory epithelial cells and lung macrophages from male and female donors will be pretreated with estradiol and then infected with influenza virus. The viral load, phospho-signaling and gene expression will be quantified, and recently developed network-based perturbation analyses will be applied to identify the top gene expression regulators. Validation studies will be performed on the top pathways and regulators to confirm their activity in the context of influenza infection in vitro. In Aim 3, using immune cell depletion, knockout mouse models and dynamical mathematical modeling, we will assess the role of monocytes in sex-specific, estradiol-regulated immune responses during influenza infection, and determine how immune regulators identified in vitro impact infection severity in vivo. Overall, this program will determine how E2 regulates the host response during influenza infection in order to alter infection outcomes and reveal what aspects of E2 regulation are sex-specific. Newly identified host factors and E2-regulated mechanisms are strong candidates for drug targeting and can lead to improved treatment based on patient sex or circulatory hormone levels.