The immune response to COVID-19: Does sex matter?

Abstract

The coronavirus disease 2019 (COVID-19) pandemic has created unprecedented challenges worldwide. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19 and has a complex interaction with the immune system, including growing evidence of sex-specific differences in the immune response. Sex-disaggregated analyses of epidemiological data indicate that males experience more severe symptoms and suffer higher mortality from COVID-19 than females. Many behavioural risk factors and biological factors may contribute to the different immune response. This review examines the immune response to SARS-CoV-2 infection in the context of sex, with emphasis on potential biological mechanisms explaining differences in clinical outcomes. Understanding sex differences in the pathophysiology of SARS-CoV-2 infection will help promote the development of specific strategies to manage the disease.

Keywords: COVID-19; SARS-CoV-2; gender; immune system; sex; sex hormones.

FIGURE 1

The life cycle of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). (1) The cycle begins with the virus entering cells of the airway. Viral attachment is mediated by the interaction between the viral spike (S) protein and host ACE2 receptors with the serine protease TMPRSS2 co‐receptors. Furin cleaves the spike protein to make it functional for priming and activation. (2) Either by endocytosis or membrane fusion, the virus enters the host cell. (3) This event is followed by the release of viral ssRNA into the host cell. The release of the viral genome triggers the signals for activation of intracellular pattern recognition receptors such as TLR7 that usually lead to the synthesis of antiviral interferons. (4 & 4′) Subsequently, the translation and cleavage of the viral polymerase protein occur in the cytoplasm. (5 & 5′) RNA replication depends on the viral RNA‐dependent RNA polymerase (RdRp). Translation of viral structural proteins occurs via the ribosomes in the endoplasmic reticulum (ER). (6) Virion assembly occurs at ER‐Golgi junctions in concurrence with (7) the formation of mature virions inside Golgi vesicles. (8) Post‐assembly, the infective virions are released via exocytosis or through cell lysis. The inset table shows possible intervention points for SARS‐CoV‐2 at multiple stages of its life cycle. These repurposed drugs intercept the SARS‐CoV‐2 infection at crucial points, including inhibiting the viral proteins or interfering with viral entry, translation of viral proteins, assembly of new virions, viral budding, etc. Many repurposed/experimental drugs also possess off‐target side‐effects contributing to drug‐induced cytotoxicity, local tissue damage, and systemic immunosuppression

FIGURE 2

The sex differences in the immune response to severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection. Males have more testosterone and dihydrotestosterone, whilst females have higher oestrogen and progesterone levels. Men experience aggravated immune responses to SARS‐CoV‐2 infection due to various factors. The expression of transmembrane serine protease 2 (TMPRSS2), which facilitates viral entry, is regulated by androgen receptors and higher in males. Males with coronavirus disease 2019 (COVID‐19) have higher neutrophil‐to‐lymphocyte ratios, lower lymphocyte count and greater serum C‐reactive protein levels. Older males have decreased naïve T and B cells. Males experience hyperinflammation and cytokine storms, which translate into increased COVID‐19 severity. In females, SARS‐CoV‐2 infection is better controlled due to the efficient sensing of the viral genome by endosomally expressed TLR7 in immune cells. TLR7 expression is enhanced by higher levels of oestrogen in females. Such intracellular detection of the viral genome in immune cells amplifies the production of type I interferon (IFN), which confers antiviral immunity. In plasmacytoid dendritic cells of females, IRF5 expression is higher, which may explain the greater production of type I IFN in females. Additionally, oestradiol promotes regulatory T cells, and women also have increased CD4+:CD8+ T‐cell ratios, which may have an impact on COVID‐19 progression. Females exhibit more robust adaptive immunity compared with males, with pronounced effects on reducing dysregulated inflammation.