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.

Heterogeneous Escape from X Chromosome Inactivation Results in Sex Differences in Type I IFN Responses at the Single Human pDC Level

“…It was furthermore suggested that early treatment with IFNα2 during initial SARS-CoV-2 infection was associated with reduced mortality ( Wang et al., 2020 ). Our data showing higher IFNα and IFNβ mRNA levels in female pDCs with biallelic TLR7 expression suggest that higher type I IFN responses in females might potentially contribute to a better control of SARS-CoV-2 infection in women ( Bunders and Altfeld, 2020 ).…”

“…A bias between females and males in the incidence and outcome of infectious diseases has been described for viral (HIV, hepatitis C virus [HCV], and influenza), bacterial (tuberculosis), and parasitic (amebiasis and leishmaniasis) infections ( Sterling et al., 2001 ; Meditz et al., 2011 ; Grebely et al., 2014 ; Hertz and Schneider, 2019 ; Bernin and Lotter, 2014 ; Hoffmann et al., 2015 ). The current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic also exhibits a sex difference with an estimated case mortality rate of 1.7 (male): 1 (female) in Europe ( Bunders and Altfeld, 2020 ; Scully et al., 2020 ). Furthermore, immune responses toward vaccines differ between women and men, with most vaccines eliciting stronger immune responses in adult females ( Flanagan et al., 2017 ).…”

Coronavirus disease 2019 in patients with inborn errors of immunity: An international study

“…Rather, differential levels of inflammatory mediators, T-cell responses, and/or virus-specific antibodies between infected males and females may explain the predominance of males with severe COVID-19. 30 …”

Sex-dependent immune response and lethality of COVID-19

“…1 ) ( Liu et al, 2010 , Tukiainen et al, 2017 ). Its sexual dimorphic human ACE2 gene expression varies in different tissues and organs, with lung and liver as two of the organs with notable male-biased ACE2 transcript levels ( Bunders and Altfeld, 2020 , Pirola and Sookoian, 2020 , Tukiainen et al, 2017 ).

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