# Sex-specific Immune Responses to Severe Influenza Virus Infection

> **NIH NIH R21** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $148,510

## Abstract

Sex-specific Immune Responses to Severe Influenza Virus Infection
ABSTRACT
Men and women experience influenza virus infection differently, with women often experiencing a more severe
infection. Lung immunopathology is a major contributing factor to influenza virus disease severity and has been
linked to differential disease outcomes in men and women. The differences between male and female immune
responses during infection are the immune response dynamics, i.e. the speed and magnitude of the reaction of
key immune molecules and cells to the virus. These dynamics are regulated by the molecular and cellular
interactions that comprise the lung immune system, and it has been shown that lung immune dynamics can be
altered in women by altering levels of circulating sex steroids (estradiol) to affect lung inflammation and overall
infection severity. Here, we propose an experimental and computational modeling study to quantify the
differential immune kinetics that drive the distinct lung immunopathological outcomes observed between men
and women. Human male and female infection outcomes have been recapitulated in mouse models. We will
infect male and female mice with a moderate pandemic H1N1 virus and a deadly avian influenza virus, collect
dynamic immunologic and hormone data, and train mathematical models to the data to quantify the immune
kinetics regulating the differential dynamic lung immune responses observed between the sexes. The
immunologic data will include major cytokines and immune cells with established significance to virus clearance
and respiratory tissue inflammation. Successful completion of the research program will provide the first sex-
specific mathematical models of influenza-induced immune responses, the first mathematical models of the
avian influenza induced immune response, and the first mathematical models quantifying the impact of sex
hormones on lung immune regulation in females. By quantifying which immune kinetics are different between
males and females during moderately and severely pathogenic infections, we will generate novel hypotheses on
the molecular/cellular origins of lung immunopathology during influenza infection and provide quantitative
evidence on whether mechanisms promoting severe lung pathology are dependent on sex, virulence of the virus,
or both factors. And quantifying the relationship between sex hormones and lung immune activity in females may
provide insight into the mechanisms associated with the increased susceptibility experienced by pregnant
women during severe influenza virus infection.

## Key facts

- **NIH application ID:** 10310516
- **Project number:** 5R21AI151418-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Jason Edward Shoemaker
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $148,510
- **Award type:** 5
- **Project period:** 2020-12-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10310516

## Citation

> US National Institutes of Health, RePORTER application 10310516, Sex-specific Immune Responses to Severe Influenza Virus Infection (5R21AI151418-02). Retrieved via AI Analytics 2026-05-30 from https://api.ai-analytics.org/grant/nih/10310516. Licensed CC0.

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