Sex and sex steroids impact influenza pathogenesis across the life course

Abstract

Males and females differ in the outcome of influenza A virus (IAV) infections, which depends significantly on age. During a typical seasonal influenza epidemic, young children (<5 years of age) and aged adults (65+ years of age) are at greatest risk for severe disease, and among these age groups, males tend to suffer a worse outcome from IAV infection than females. Following infection with either pandemic or outbreak strains of IAVs, females of reproductive ages (i.e., 15-49 years of age) experience a worse outcome than their male counterparts. Among females of reproductive ages, pregnancy is one factor linked to an increased risk of severe outcome of influenza, although it is not the sole factor explaining the femalepreponderance of severe disease. Small animal models of influenza virus infection illustrate that inflammatory immune responses and repair of damaged tissue following IAV infection also differ between the sexes and impact the outcome of infection. There also is growing evidence that sex steroid hormones, including estrogens, progesterone, and testosterone, directly impact immune responses during IAV infection to alter outcomes. Greater consideration of the combined effects of sex and age as biological variables in epidemiological, clinical, and animal studies of influenza pathogenesis is needed.

The humanized DRAGA mouse (HLA-A2. HLA-DR4. RAG1 KO. IL-2R g c KO. NOD) establishes inducible and transmissible models for influenza type A infections

“…48 Conversely, several reports claimed that the male testosterone was associated with higher sensitivity to influenza infection in wild-type mice. [49][50][51] These observations are consistent with studies by Sutherland et al showing that androgen blockade in mice and humans supports thymic regeneration, 52 which in turn enhances HIS reconstitution following HSC transplantation. 53 However, studies by Nowak et al suggested that different fractions of the androgen hormones in humans afflicted by IAV infections are modulatory, rather than implicitly immunosuppressive.…”

Pre-exposure to anti-TNFα decreases COVID-19 symptoms: a multicentre retrospective cohort study

“…The severity of COVID-19 symptoms shows clear sex differences with more severe cases and higher mortality reported in men than women [9]. Similar sex differences were revealed in the outcome of influenza A virus infections probably mediated by the impact of sex steroid hormones in immune responses [21]. Although the studied population was not sex-balanced (1592 women vs 902 men) our analyses stratified by sex also revealed potential sex differences in the effects of several immunomodulatory compounds.…”

What’s Sex Got to Do With COVID-19? Gender-Based Differences in the Host Immune Response to Coronaviruses

“…Given the wide variations in human versus rodents in vitro versus in vivo systems, epidemiological studies have shown that there is not a universal paradigm regarding the role of gender or sex hormones on the immune response to respiratory viruses. It is hypothesized that the disease outcomes are ultimately a combination of the magnitude of the immune response and degree of host tissue damage ( 92 , 93 ). There is a male bias when a weaker immune response contributes to damage, while a female bias may occur due to a stronger immune response that causes damage.…”