COVID-19 pandemic: insights into molecular mechanisms leading to sex-based differences in patient outcomes

Abstract

Recent epidemiological studies analysing sex-disaggregated patient data of coronavirus disease 2019 (COVID-19) across the world revealed a distinct sex bias in the disease morbidity as well as the mortality - both being higher for the men. Similar antecedents have been known for the previous viral infections, including from coronaviruses, such as severe acute respiratory syndrome (SARS) and middle-east respiratory syndrome (MERS). A sound understanding of molecular mechanisms leading to the biological sex bias in the survival outcomes of the patients in relation to COVID-19 will act as an essential requisite for developing a sex-differentiated approach for therapeutic management of this disease. Recent studies which have explored molecular mechanism(s) behind sex-based differences in COVID-19 pathogenesis are scarce; however, existing evidence, for other respiratory viral infections, viz. SARS, MERS and influenza, provides important clues in this regard. In attempt to consolidate the available knowledge on this issue, we conducted a systematic review of the existing empirical knowledge and recent experimental studies following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The qualitative analysis of the collected data unravelled multiple molecular mechanisms, such as evolutionary and genetic/epigenetic factors, sex-linkage of viral host cell entry receptor and immune response genes, sex hormone and gut microbiome-mediated immune-modulation, as the possible key reasons for the sex-based differences in patient outcomes in COVID-19.

Keywords: COVID-19; SARS-CoV-2; epigenetic mechanisms; evolution; genetics; sex; sex hormones.

Fig. 1.

COVID-19 sex-disaggregated data at a global scale. Data source: The COVID-19 Sex-Disaggregated Data Tracker, Global health 50/50 (https://globalhealth5050.org, an open access database. The data were reviewed until 21 April 2021).

Fig. 2.

Virus-mediated modulation of RAS in COVID-19 patients and influence of sex hormones. ACE2 and its analogue ACE are key molecular regulators of RAS, which regulates blood pressure, fluid and electrolyte balance and systemic vascular resistance. ACE2 competes with its analogue ACE to keep a balance of the pathways regulating these functions. ACE2 metabolises Ang II to Ang 1–7 which further act through Mas1R present in lung epithelial cells favouring vasodilatation, anti-inflammation and antifibrosis. Conversely, an ACE prevents metabolising Ang II which further acts on its cognate receptor AT1R favouring vasoconstriction, fibrosis and increased inflammation. SARS-CoV-2 potentially downregulates ACE2 (but not ACE) in the infected epithelial cells thus favours an ACE/Ang II/AT1R-mediated pathway leading to vasoconstriction, lung fibrosis and increased inflammation resulting in increased disease severity. Sex hormones can effectively modulate RAS axis influencing severity of disease in COVID-19 patients. Higher serum levels of oestrogen in females plausibly downregulates ACE and AT1R, and upregulates ACE2 and Mas1R, thus favours ACE2/Ang 1–7/Mas1R-mediated regulation of RAS resulting in less severe disease. Conversely, higher serum levels of testosterone in male produces an opposite effect. Testosterone by regulating expression of TMPRSS2 gene through AR causes increased internalisation of ACE2: SARS-COV-2 complex. The increased consumption of ACE2 by SARS-CoV-2 causes its depletion on epithelial cells thus activating the ACE/Ang II/AT1R-mediated pathway favouring vasoconstriction, increased tissue inflammation and fibrosis resulting in severe COVID-19. ACE, angiotensin converting enzyme; Ang II, angiotensin II; AT1R, angiotensin type II receptor 1; Mas1R, Mas1 proto-oncogene, G protein-coupled receptor.

Fig. 3.

Tissue-specific distribution (m-RNA and protein) of SARS-CoV-2 host cell entry receptor (ACE2) and related proteases (TMPRSS2, FURIN and ADAM17) in reproductive system components in men. A high expression (m-RNA and/or proteomic) of ACE2 and significantly increased expression of the one or more proteases is observable in multiple cellular/tissue components indicating their high susceptibility for the SARS-CoV-2 infection. Data source: Human Protein Atlas (https://www.proteinatlas.org/humanproteome/sars-cov-2, an open access database).

Fig. 4.

Tissue-specific distribution (m-RNA and protein) of SARS-CoV-2 host cell entry receptor (ACE2) and related proteases (TMPRSS2, FURIN and ADAM17) in reproductive system components in women. A low or non-detectable m-RNA and/or proteomic expression of ACE2, however, significant expression of one or more proteases is observable across the tissues, indicating their low susceptibility for SARS-CoV-2 infection. Data source: Human Protein Atlas (https://www.proteinatlas.org/humanproteome/sars-cov-2, an open access database).

Fig. 5.

Schematic representation of the role of evolution, genetics, epigenetic mechanisms and sex hormones in sex-based differences in COVID-19 outcomes. Females bear two X chromosomes, of which one gets inactivated during oogenesis through epigenetic silencing of the genes – this phenomenon is known as ‘X-chromosomal inactivation’ (XCI). Some of the X-linked genes escape XCI, among these are the key immune functions genes, such as ACE2, TLRs-7, -8, ILs-4, -10 and -13, FoxP3, CD40L, IRAK1 and NEMO, thus these genes express in females in double dosage in comparison with males. These immune genes not only prime the females for a stronger immune response against infectious agents, but also prevent against hyper-inflammatory responses, such as CS. Apart from this, certain immune genes have sex hormone-specific regulatory elements in their promoter region modulating their expression, such as oestrogen has for IFN, and TMPRSS2 has for TMPRSS2. A marked influence of sex hormones on the formation of cytokines has also been noted, such as testosterone induces greater syntheses of Th-17 cells and in turn release of pro-inflammatory markers in males, such as IL-17, IL-20 and CCL-20 – thus favour hyper-inflammatory responses and in turn poor clinical outcomes. XCI, X chromosome inactivation; ACE2, angiotensin-converting enzyme 2; TMPRSS2, transmembrane protease, serine 2; ARE, androgen receptor element; SRY, sex-determining region Y; SOX-9, SRY-box transcription factor-9; TLRs, Toll-like receptors; IFN, interferon; ILs, interleukins; FoxP3, forkhead box P3; CD40L, cluster of differentiation 40L; CCL-20, chemokine (C–C motif) ligand-20; IRAK1, interleukin-1 receptor-associated kinase 1; NEMO, NF-κB essential modulator.

Fig. 6.

Immunological basis of sex-based differences in COVID-19 outcomes. A stronger protective immune response, for its each component: TLR-based viral sensing, and innate and adaptive immunity, is ensued against SARS-CoV-2 infection in females in comparison with males. TLR, Toll-like receptor; IFN, interferon; ISGs, interferon-stimulated genes; ILs, interleukins; IRF, interferon regulatory factor; CD, cluster of differentiation; RORγt, retinoic acid-related orphan receptor gamma-t; MAVS, mitochondrial antiviral signalling protein; IRAK, interleukin-1 receptor-associated kinase; TRAF, TNF receptor (TNFR) associated factor; TBK, TANK-binding kinase; MyD88, myeloid differentiation primary response gene 88.

Fig. 7.

Summary of the molecular mechanisms leading to sex-differentiated outcomes in COVID-19 patients. The sex-based differences primarily occur at the level of viral cell entry receptors and immune response mechanisms against the infection. Sex-specific genetic and epigenetic factors, and also sex hormones differentially modulate viral cell entry receptors and associated host proteases, viral sensing receptors and multiple immune response genes including IFN. Some other factors, such as smoking and gut microbiome have also been found to influence the patient outcomes in a sex-based manner. XCI, X chromosome inactivation; ACE2, angiotensin-converting enzyme 2; TMPRSS2, transmembrane protease, serine 2; CTSL, cathepsin L; ARE, androgen receptor element; SRY, sex-determining region Y; SOX-9, SRY-box transcription factor-9; TLRs, Toll-like receptors; IFN, interferon; IRAK1, interleukin-1 receptor-associated kinase 1; ISGs, interferon-stimulated genes; IRF-interferon regulatory factor; TRAF, TNF receptor (TNFR) associated factor; TRIF, TIR-domain-containing adapter-inducing interferon-β; MyD88, myeloid differentiation primary response gene 88.