Turns out that there is a biological reason why women and men suffer viral infections like influenza differently – and a team of engineers, immunologists, and virologists at the University of Pittsburgh and University of Wisconsin, Madison are extending their research to better understand why and how to design better, possible sex-specific treatments.

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Jason Shoemaker, associate professor of chemical engineering at Pitt’s Swanson School of Engineering, is fascinated by how sex differences affect human immune responses to respiratory infections, like the flu and COVID. His third project in this realm, “Predictive Modeling of Estradiol Effects and Sex Differences on Immunopathology During Influenza Infection,” recently received a nearly $3.8 million R01 award from the National Institutes of Health and its Institute of Allergy and Infectious Diseases to develop mathematical models that identify these differences, and precision medicine-based therapeutics that improve treatment.

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“While there are a lot of anecdotal stories about how men and women respond to respiratory diseases, the research shows that women are more likely to have a more serious response to some viruses,” Shoemaker explains. “However, we’re not sure how hormones impact the immune system. Specifically for flu, there is strong evidence that women 18-40/45 years old are more likely to experience severe infection, even though demographically they tend to be the healthiest.”

Immune response

Shoemaker, who directs the Immunosystems Lab at Pitt, has previously modeled respiratory infections to better understand how the immune system reacts—or overreacts—to a virus, including modeling age- and sex-specific immune responses. Most recently his group studied how estradiol, a female sex hormone, could impact immune response.

“Animal studies have shown that hormones potentially affect the outcome of infection, specifically in the lungs,” he notes. “In part two of this project, we’ll examine human respiratory cells and lung macrophages from male and female donors that are exposed to estradiol and then infected with influenza virus. Mathematical models will enable us to integrate the data.”

Through this computational modeling, Shoemaker’s group hopes to identify the molecules or pathways that are affecting the cells and begin to identify potential treatments that are personalized to a person’s sex or hormone levels.

Hormones and chromosomes

“Typical treatments for respiratory infections are homogenous, but if hormones and chromosomes indeed create a different immune response between men and women, then we need to develop more targeted therapies,” Shoemaker says. “The impact of the Covid-19 pandemic gave us tremendous amounts of data to better understand the immune system, and advances in computational modeling reduce trial and error in developing more effective treatments.”

Shoemaker’s Pitt and Wisconsin co-investigators include:

  • John Alcorn, University of Pittsburgh, Dept of Immunology & Dept of Pediatrics
  • William Hawse, University of Pittsburgh, Dept of Immunology
  • Amie Eisfeld, Department of Pathobiological Sciences, University of Wisconsin, Madison, WI
  • Yoshihiro Kawaoka, Department of Pathobiological Sciences, University of Wisconsin, Madison, WI

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