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

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $763,312

## Abstract

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.

## Key facts

- **NIH application ID:** 10980709
- **Project number:** 1R01AI180382-01A1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Jason Edward Shoemaker
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $763,312
- **Award type:** 1
- **Project period:** 2024-06-18 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10980709

## Citation

> US National Institutes of Health, RePORTER application 10980709, Predictive Modeling of Estradiol Effects and Sex Differences on Immunopathology during Influenza Infection (1R01AI180382-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10980709. Licensed CC0.

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