Viral cellular receptor and the severity of COVID-19 illness
The binding of the viral spike protein to the specific cellular receptor on the membrane is the first step of viral infection, followed by fusion with the cell membrane. The lung epithelial cells represent the primary target of coronaviruses. The binding of the virus spikes initiates SARS-CoV entry into target cells via receptor-binding domain to the cellular receptor, which has been identified as ACE2 (Jaimes, Millet, Stout, Andre & Whittaker, 2020; Wan, Shang, Graham, Baric & Li, 2020). Importantly, the sequence of the receptor-binding domain in spikes of SARS-CoV-2 is similar to that of SARS-CoV. The sequence data shows similarities between SARS-CoV-2 and SARS-CoV and the recent reports strongly suggest that the entry of SARS-CoV-2 to the host cells is via ACE2 receptor (Hoffmann et al., 2020; Wan, Shang, Graham, Baric & Li, 2020). The ACE2 gene is mapped on the human X chromosome (Xp22) (Egan, 2013; Tipnis, Hooper, Hyde, Karran, Christie & Turner, 2000). The hormone 17 β -estradiol increased ACE2 protein, and gene expression in ovariectomized female rats with the renal wrap model of hypertension. It also prevented glomerular and tubular injury in this experimental hypertensive model (Ji, Menini, Zheng, Pesce, Wu & Sandberg, 2008). Previous studies on SARS-CoV reported that the binding of viral Spike (S) protein to ACE2 down-regulates the expression of ACE2, resulting in a diminished protective role of ACE2 and, subsequently, acute respiratory failure (Kuba et al., 2005). Furthermore, ACE2 expression is dramatically reduced with aging in both genders, (Xie, Chen, Wang, Zhang & Liu, 2006). Taken together, the malfunction or the down-regulation of the ACE2 receptor on the cell membrane during SARS-CoV-2 represents one of the leading causes of developing severe COVID-19 illness.
Additionally, ACE2 receptor is co-expressed with TMPRSS2, a cellular trans-membrane protease that cleaves the S protein of SARS-CoV and SARS-CoV-2 into two fragments S1, which is essential for virus attachment, and S2, for virus fusion into the target cells (Bertram et al., 2013; Glowacka et al., 2011; Hoffmann et al., 2020; Zmora, Moldenhauer, Hofmann-Winkler & Pohlmann, 2015). TMPRSS2 protein is expressed in many tissues, including the lungs. In lung tissues, TMPRSS2 protein is expressed primarily in the epithelial cells (Jacquinet, Rao, Rao & Hoidal, 2000; Lin et al., 1999). The expression levels of TMPRSS2 protein are regulated by levels of androgen and androgen receptors (Chen et al., 2010; Lin et al., 1999; Tomlins et al., 2008; Yu et al., 2010), suggesting sex-related expression levels of TMPRSS2 protein. Both women and children have a lower level of androgen and androgen receptors than men, and therefore, TMPRSS2 may play a critical role in the severity of COVID-19 pathogenesis in men. This pattern is followed when we looked at percentage of age and gender distribution of people died out of total deaths in United States due to COVID-19 (Fig. 1 ) (CDC, 2020). Where we saw a positive correlation in increase in % of people died out of total death due to COVID-19 with increase in age group distribution. In USA, the percentage of death of male is also higher compared to female COVID-19 patients. Thus, it could be possible that the expression levels of ACE2 and TMPRSS2 have an impact on virus infectivity and pathogenesis among different groups of individuals, considering the variation in the expression levels in older men compared to the women and children.
The possible role of viral secondary receptors and cell-to-cell virus transmission could have an impact on the severity and mortality of COVID-19 infection. Wang et al. reported that SARS-CoV-2 is able to infect T- lymphocyte cell lines that express a deficient level of ACE2 surface receptor, but failed to reproduce progeny viruses, which indicates some other cellular receptors may play a role in the cellular entry of the virus (Wang et al., 2020c). Currently, a clinical trial (NCT04275245) is going on to test the efficacy of Meplazumab against SARS-CoV-2.