A gendered magnifying glass on COVID-19

Abstract

COVID-19 pandemia is affecting Countries worldwide with a gendered death excess as being a male represents, especially in the 50-69 years age group, an unfavourable factor. Females are constitutionally prone to defend themselves against pathogens with a stronger efficiency than males. As a fact, several genes involved into the regulation of the innate and adaptive immune response are strategically placed on the X-chromosome and, among them, pathogen-related receptors (PRRs), such as Toll-like receptor 7, suitable to recognize ssRNAs and trigger a gendered successful anti-viral fight. On the other hand, a more regulated IL-6 production and a more contained inflammation after the encounter of a pathogen supply score points in favour of the female sex in the view that an abnormal and exaggerated cytokine release does represent the hallmark of the deathful SARS-CoV-2 infection. The sex-prevalent expression of the attachment and permissive molecules ACE2 and TMPRSS2 further supports the concept of a male-oriented vulnerability. In this review, the possible role of biological and immunological sex differences into the higher morbidity and mortality of SARS-CoV-2 between females and males are discussed.

Keywords: COVID-19; Female; Gender; IL-6; SARS-CoV-2; Sex; TLR7; X chromosome.

Fig. 1

ACE2 and COVID-19. a The renin angiotensin system (RAS) and the role of ACE2 in SARS-CoV-2 infection in brackets the year of discovery; b the different balance of ACE2 expression in males and females. ACE2: Angiotensin I Converting Enzyme 2; AT₁R angiotensin receptor type 1, AT₂R angiotensin receptor type 2

Fig. 2

TLR7 within the X chromosome and its principal characteristics in the anti-viral response. The Toll-like Receptor 7 gene (TLR7) is located in the pseudo-autosomal region 1 of the X chromosome (p22.2). The principal characteristics of TLR7 are summarized on the right. ACE2: Angiotensin I Converting Enzyme 2; BTK: Bruton Tyrosine Kinase; CD40LG: CD40 Ligand; CFP: Complement Factor Properdin; CYBB: Cytochrome B-245 Beta Chain; CXCR3: C-X-C Motif Chemokine Receptor 3; GATA1: GATA Binding Protein 1; IKBKG: Inhibitor of Nuclear Factor Kappa B Kinase Regulatory Subunit Gamma; IL13RA1: Interleukin 13 Receptor Subunit Alpha 1; IL2RG:Interleukin 2 Receptor Subunit Gamma; IARK1: Interleukin 1 Receptor Associated Kinase 1; IRF Interferon regulatory factors; FOXP3: Forkhead Box P3; LGP2 laboratory of genetic and physiology 2; MAPK mitogen-activated protein kinase; MDA5 melanoma differentiation-associated protein 5; MyD88 myeloid differentiation primary response gene 88; NFκB nuclear factor kappa-light-chain-enhancer of activated B cells; pDCs plasmacytoid dendritic cells; RIG-I retinoic acid-inducible gene I; TLR8: Toll Like Receptor 8; WAS: Wiskott-Aldrich Syndrome