Armed with estrogens, female cells are better poised to fight the flu

NIAID CEIRS | Research Publication Commentary

Peretz, J, et al. Estrogenic compounds reduce influenza A virus replication in primary human nasal epithelial cells derived from female, but not male, donors. Am J Physiol Lung Cell Mol Physiol. (2015).

It seems that the playing field is not entirely even between the sexes when it comes to fighting off influenza. Males and females display distinct susceptibilities to infectious diseases and inflammatory disorders, likely due to a variety of factors including genetics and differences in the circulation of hormones. These differences are perhaps underappreciated and underutilized in the study and treatment of infectious diseases. Estrogen, a hormone critical for female reproductive health and development, has been shown to convey anti-viral effects against several pathogens including HIV, Hepatitis C, Ebola virus, and human cytomegalovirus, but its precise role in the susceptibility to and defense against influenza at the cellular level was unknown.

Respiratory epithelial cells lining the airway serve as a site of entry for influenza A viruses to infect and grow in the human body. This process involves a delicate balance between the virus’ ability to reproduce and the host’s ability to fight off infection. Dr. Jackye Peretz and colleagues from Johns Hopkins Center of Excellence for Influenza Research and Surveillance (CEIRS) examined the ability of an influenza A H3N2 virus to replicate in human nasal epithelial cells from male or female donors that had been exposed to one of three treatments: estrogen; estrogen mimics called Selective Estrogen Receptor Modulators (SERMs); or bisphenol A, an estrogen-like compound found in some manufactured plastics. Treatment with estrogen or select estrogen mimics prior to infection enabled epithelial cells from female donors, but not male donors, to better control infection as measured by decreased viral growth.

Cells sense estrogen through the use of multiple receptors, resulting in direct or indirect changes in gene expression. The authors analyzed gene expression following stimulation of different receptors found in nasal cells isolated from male and female donors to investigate how estrogen reduces viral replication. They identified that estrogen receptor 2 (ESR2) is likely responsible for the antiviral effect, as the expression of the ESR2 gene itself was selectively increased in female cells treated with estrogen. Global differences in the host response to infection with and without estrogen included decreased expression of genes associated cell metabolism and also reduced expression of a family of zinc finger proteins that have not previously been implicated in influenza virus infection.

This study is the first to define a protective role for estrogen during infection of human cells with influenza A viruses. Additionally, these results shed light on the mechanisms through which estrogenic compounds impact viral replication, and perhaps have broader implications for other viral pathogens. Although this study focused on infection in nasal epithelial cells, impaired viral replication may translate to reduced symptoms and spread of disease in people. While these findings likely do not explain or reveal broad differences in the susceptibility to and severity of influenza virus infection in men versus women because of the natural fluctuation in estrogen and other sex hormone levels, it hints at an added benefit of the estrogenic compounds used in hormone replacement therapy, infertility treatment, and contraception. Thus, it provides a promising avenue for enhancing host protection against influenza in women.

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