Sex and the flu

Pitt and Wisconsin researchers seek to understand how hormones impact influenza in men and women

Grant and Award Announcement

University of Pittsburgh

 

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Jason Shoemaker, associate professor of chemical engineering at Pitt’s Swanson School of Engineering

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Credit: Swanson School of Engineering

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.

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.

“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,”1,2,3 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.”4

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.

“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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1 Sex Differences in Influenza: The Challenge Study Experience. Giurgea LT, Cervantes-Medina A, Walters K, Scherler K, Han A, Czaikowski LM, Baus HA, Hunsberger S, Klein SL, Kash JC, Taubenberger JK, Memoli MJ. J Infect Dis. 2021 Aug 23;jiab422. doi: 10.1093/infdis/jiab422.

2 Mechanisms of sex disparities in influenza pathogenesis. Klein SL, Hodgson A, Robinson DP. J Leukoc Biol. 2012 Jul;92(1):67-73. doi: 10.1189/jlb.0811427. Epub 2011 Nov 30. PMID: 22131346; PMCID: PMC4046247.

3 Klein S. L., Pekosz A., Passaretti C., Anker M., Olukoya P. (2010) Sex, Gender and Influenza. World Health Organization, Geneva, 1–58.

4 Eshima N, Tokumaru O, Hara S, Bacal K, Korematsu S, Tabata M, Karukaya S, Yasui Y, Okabe N, Matsuishi T. Sex- and age-related differences in morbidity rates of 2009 pandemic influenza A H1N1 virus of swine origin in Japan. PLoS One. 2011 Apr 29;6(4):e19409. doi: 10.1371/journal.pone.0019409. PMID: 21559366; PMCID: PMC3084848.