The immune–endocrine interplay in sex differential responses to viral infection and COVID-19, 2024, Valentino D’Onofrio

Highlights

• Male sex is an independent risk factor for severe acute COVID-19, while female sex is an independent risk factor for post-acute sequelae of COVID-19 (PASC).
• The male sex hormone testosterone increases FOXP3 expression, regulatory T cell differentiation, and transforming growth factor β (TGFβ) production while suppressing the production of proinflammatory cytokines. The relationship between high testosterone and decreased inflammation, which is observed during acute SARS-CoV-2 infection in males, might help to explain the milder course of acute disease in males than in females.
• The female sex hormone estradiol increases plasma concentrations of interleukin (IL)-12p40 and IL-23, promoting the differentiation of T cells into Th1 and Th17, and inducing interferon γ (IFNγ) production. Estradiol induces somatic hypermutation leading to heightened antibody affinity maturation. Conversely, higher estradiol concentrations may result in higher SARS-CoV-2-specific antibody and autoantibody production and more exhausted CD8+ T cells that are associated with PACS.

Significance
Sex hormones are associated with different clinical and immunological outcomes of viral infections by generally modulating transcriptional and epigenetic processes in innate and adaptive immune cells. This can lead to altered differentiation and effector functions in these cells. Deciphering the transcriptional and epigenetic molecular cascades that are triggered by sex hormones in innate and adaptive immune cells is needed to fully understand the sex-dependent differences in the outcomes of viral infections such as SARS-CoV-2.
Abstract
Men are at higher risk for developing severe COVID-19 than women, while women are at higher risk for developing post-acute sequelae of COVID-19 (PASC). This highlights the impact of sex differences on immune responses and clinical outcomes of acute COVID-19 or PASC. A dynamic immune–endocrine interface plays an important role in the development of effective immune responses impacting the control of viral infections. In this opinion article we discuss mechanisms underlying the transcriptional and epigenetic regulation of immune responses by sex hormones during viral infections. We propose that disruption of this delicate immune–endocrine interplay can result in worsened outcomes of viral disease. We also posit that insights into these immune mechanisms can propel the development of novel immunomodulatory interventions that leverage immune–endocrine pathways to treat viral infections.
LINK