Implications of Sex Differences in Immunity for SARS-CoV-2 Pathogenesis and Design of Therapeutic Interventions

Abstract

Men present more frequently with severe manifestations of coronavirus disease 2019 (COVID-19) and are at higher risk for death. The underlying mechanisms for these differences between female and male individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are insufficiently understood. However, studies from other viral infections have shown that females can mount stronger immune responses against viruses than males. Emerging knowledge on the basic biological pathways that underlie differences in immune responses between women and men needs to be incorporated into research efforts on SARS-CoV-2 pathogenesis and pathology to identify targets for therapeutic interventions aimed at enhancing antiviral immune function and lung airway resilience while reducing pathogenic inflammation in COVID-19.

Keywords: COVID-19; SARS-CoV-2; immune responses; sex differences; tissue regeneration.

Figure 1

Sex Differences in Immune-Mediated Antiviral and Tissue Repair Mechanisms in COVID-19 Sex-specific differences in immune-mediated antiviral mechanisms are described on the left and tissue repair mechanisms on the right. Left: SARS-CoV-2 binds to ACE2 receptors to gain entrance into cells. SARS-CoV-2 can be sensed by TLR7 and TLR8 and induce the production of type I IFNs by pDCs. Tfh cells provide help through cytokines and CD40/CD40L to B cells that produce neutralizing antibodies against SARS-CoV-2. These antiviral mechanisms are stronger in females and might be partially regulated by higher expression of genes encoded by the X chromosome, including TLR7, TLR8, and CD40L. Right: Th22 cells and ILC2s produce cytokines (IL-22, IL-5, IL-13, and AREG) that promote lung airway epithelial cell growth and function. Stronger Treg cell and ILC2 function as well as higher expression of IL-13R in women might promote lung airway tissue resilience and function in SARS-CoV-2-infected women. Molecules encoded by genes located on the X chromosome are shown in red, including ACE2, TLR7, TLR8, CD40L, and IL-13R. Wedges on the bottom of the figure represent overall higher immune-mediated antiviral and tissue repair mechanisms in women compared to men.