COVID-19 and ACE2 in the Liver and Gastrointestinal Tract: Putative Biological Explanations of Sexual Dimorphism

Dear Editors:

The presence of severe acute respiratory disease coronavirus-2 (SARS-CoV-2) gastrointestinal infection has recently been reported by 2 independent groups from China.^{1 , 2} Also, liver injury, in part presumably explained by viral infection of liver cells, may be present in about 60% of infected patients.³ Therefore, patients with chronic liver disease may be vulnerable to the serious clinical consequences of coronavirus disease-9 (COVID-19). Likewise, emerging clinical data suggest that males with comorbidities, including obesity, are more likely to present severe disease.^{4 , 5} Although the biological mechanisms behind this observation are unclear, it has been speculated that sex-based immunologic and/or hormonal differences may account in part for that.

There is evidence highlighting angiotensin-converting enzyme 2 (ACE2) as one of the host receptors for cell entry of members of the SARS-CoV group, including SARS-CoV-2.⁶ Structural analysis showed several binding motifs between the SARS-CoV spike protein receptor-binding domain and human ACE2.⁶ Beside its role in catalyzing the cleavage of angiotensin I into angiotensin 1–9, and angiotensin II into the vasodilator angiotensin 1–7, ACE2 is involved in cellular pathways associated with other viral entry into host cells.

Gene expression levels of ACE2 differ across the human body. The highest expression levels are in the small intestine and terminal ileum, and ACE2 expression levels in the liver and lung are much lower than that of the gastrointestinal tract. One remarkable aspect of the ACE2 is that the gene maps on the nonpseudoautosomal, that is, the X-specific region of the chromosome X (Xp22.2). It is largely known that, to balance the dosage effect of X-linked genes, 1 of the 2 X chromosomes is randomly inactivated in females during development; this process is called X inactivation. Nevertheless, although most genes are silenced, about 15% of X-linked human genes escape from inactivation.⁷ More important, X escape is not uniform across different tissues. In fact, it was shown that approximately 10% of gene escape occurs selectively in specific tissues.⁷ These molecular aspects are of medical importance because they could explain sex differences in the natural course of human diseases, including COVID-19.

A recent systematic survey of the landscape of human X-linked genes inactivation using RNA sequencing-based approaches showed that ACE2 presents remarkable differences in male–female expression levels.⁸ Tukiainen et al⁸ suggested that tissue differences in X escape can directly translate into tissue-specific sex biases in gene expression.⁸ Specifically, the study showed not only that ACE2 is among the 82 X-escaping genes, but also highlighted that there might be differences in the liver and lung ACE2 expression levels between males and females.⁸ Paradoxically, escape of ACE2 from X inactivation resulted in low levels of expression in the liver, lung, and visceral adipose tissue of women.⁸ Conversely, ACE2 expression levels in colon transverse and subcutaneous adipose tissue were significantly higher in females than males.⁸

Collectively, these novel observations may have important clinical implications for patients with COVID-19. First, differences between men and women in liver ACE2 expression levels may help to explain potential clinical differences in the course of COVID-19 in patients with underlying chronic liver disease. Second, differences between men and women in ACE2 expression levels in gastrointestinal tissues due to escaping from X inactivation, including the colon, could result in different transmission patterns, including fecal–oral transmission. Third, sex-linked differential expression levels in adipose tissue and/or visceral fat might also shed light into potential differences in the odds of presenting severe complications and in-hospital death associated with comorbidities, including severe obesity.