Sex differences in viral entry protein expression, host responses to SARS-CoV-2, and in vitro responses to sex steroid hormone treatment in COVID-19

Abstract

Epidemiological studies suggest that men exhibit a higher mortality rate to COVID-19 than women, yet the underlying biology is largely unknown. Here, we seek to delineate sex differences in the expression of entry genes ACE2 and TMPRSS2, host responses to SARS-CoV-2, and in vitro responses to sex steroid hormone treatment. Using over 220,000 human gene expression profiles covering a wide range of age, tissues, and diseases, we found that male samples show higher expression levels of ACE2 and TMPRSS2, especially in the older group (>60 years) and in the kidney. Analysis of 6,031 COVID-19 patients at Mount Sinai Health System revealed that men have significantly higher creatinine levels, an indicator of impaired kidney function. Further analysis of 782 COVID-19 patient gene expression profiles taken from upper airway and blood suggested men and women present profound expression differences in responses to SARS-CoV-2. Computational deconvolution analysis of these profiles revealed male COVID-19 patients have enriched kidney-specific mesangial cells in blood compared to healthy patients. Finally, we observed selective estrogen receptor modulators, but not other hormone drugs (agonists/antagonists of estrogen, androgen, and progesterone), could reduce SARS-CoV-2 infection in vitro.

Immunological aspects and gender bias during respiratory viral infections including novel Coronavirus disease‐19 (COVID‐19): A scoping review

“…6 In addition to the significant differences between women and men in immune response, nonimmune components, like autophagy, mitochondrial functionality, and cholesterol biosynthesis have marked changes that contribute to the unique response trajectories 12 against the COVID-19. Gene expression studies 13 conducted using individual expression profiles obtained from upper airway and blood have already identified profound discrepancies in the responses to SARS-CoV-2 infection. The COVID-19-infected male patients have an increased risk of cardiovascular complications, leading to increased mortality.…”

Better COVID-19 Intensive Care Unit survival in females, independent of age, disease severity, comorbidities, and treatment

“…Estrogen in females, for instance, can have immune-enhancing effects, while testosterone in males can exert immune-suppressive effects. Furthermore, the expression of receptors that determine viral cell entry, such as transmembrane protease serine 2 (TMPRSS2) and angiotensin-converting enzyme (ACE), is affected by sex hormones and lower in females than in males 40 – 44 . TMPRSS2 is enhanced by testosterone and may play a role in delayed viral clearance 41 , 42 , whereas the ACE2 receptor, exerting protective effects in the heart, lungs, kidneys, and guts by deactivating the effects of the renin-angiotensin system (RAS) 51 , is encoded on the X chromosome and downregulated by estrogens.…”

Immunoreactivity of the SARS-CoV-2 entry proteins ACE-2 and TMPRSS-2 in murine models of hormonal manipulation, ageing, and cardiac injury

“…Conversely, preliminary data from the UK-based COVID Symptom Study indicate that HR therapy was positively associated with COVID-19 severity 24 , and no increased risk of COVID-19 related mortality was seen in women with gynecologic cancers 25 . Finally, in vitro as well as clinical data showed a reduction of SARS-CoV-2 infection by selective estrogen receptor modulators, but not by agonists/antagonists of estrogen, androgens, or progesterone 26 , 27 .…”