**5. Viral ACE2 receptor polymorphism and coronavirus infection**

ACE2 gene variants are still possible to affect SARS-CoV-2 infectivity. In SARS-CoV, the function of the S1 domain of the S protein is to mediate the binding of ACE2 receptors while the S2 domain is potentially undergoing post binding transconformational modulations which activate the fusion to the cell membrane [75]. The viral (RBD) found in S1 has been adjusted to amino acid number 270 to 510 [76]. The Leu584Ala point mutation of ACE2 significantly weakened the shedding activity of the enzyme and promoted the entrance of SARS-CoV into the host cells [77]. An ACE2 soluble form lacks the transmembrane and cytoplasmic domain was stated able to prevent SARS-CoV S protein binding to ACE2 [46]. Recombinant SARS-CoV-2 spike proteins were observed to downregulated ACE2 expression by releasing sACE2 and thus enhancing injury of the lung [78]. SARS-CoV and SARSCoV-2 participate in the identity of 76% of the amino acid residues necessary for binding of ACE2 within the SARS-CoV-2 spike S1 domain. A lot of amino acid residues of the ten human ACE2 proteins were compared by multiple sequence alignment, a 100% identity among the ACE2 sequences was observed in four different ACE2 isoforms. The role of these ACE2 isoforms remains unpredictable in SARS-CoV-2 infection outcome. According to the work by Cao et al., [61] 32 polymorphisms of ACE2, including 7 hotspot variables (Ile486Val, Lys26Arg, Asn638Ser, Asn720Asp, Ser692Pro, Ala627Val, and Leu731Ile/Phe) were identified in different peoples, that make some individuals could be more or less susceptible to the virus than others.

In a preliminary study, the distribution of the allele frequency for 1700 polymorphisms in the ACE2 gene was conducted between various populations of the world. What is noteworthy is that 11 common and rare variants were detected linked to the high ACE2 expression. It was observed that their expression is irregularly distributed among different populations groups. This study found that the polymorphism of the ACE2 gene (variant 4,646,127) was closely related to the higher expression levels of the ACE2 gene in the East Asian population, and this paved the way to study this important issue more specifically [61]. These results were confirmed by a similar subsequent study by [79], which also evidenced that the allele frequency of these variants associated with overexpression of ACE2. Also, different ACE2 polymorphisms encoded a number of proteins for SARS-CoV-2 spike protein has

*Genetic Variation*

entry by SARS-CoV-2 [47] (**Figure 1**).

**3. ACE2 expression in human tissues**

protease 2 (TMPRSS2), together with lysosomal cathepsins, considers one of the most crucial proteases in this approach [44]. Moreover, a type 1 membrane-bound enzyme (furin), also splits the site between SARS-CoV-2 spike protein (both S1 and S2 subunits). Most significantly, furin can be expressed in numerous organs, involving the lungs. Furin stimulates the splitting of spike protein (S1/S2) after the binding of SARS-CoV-2 to ACE2 receptor, and this stimulation by itself is necessary to enter the virus into the cell [45]. This different pathway, which includes furin-mediate activation, would allow SARS-CoV-2 to be less dependent on co-expressions of TMPRSS2 on the cell surface of the infect cells. Hence, SARS-CoV-2 could be able to enter a wide range of low TMPRSS2 expressing cells. Lastly, disintegrin and metalloproteinase domain-containing protein 17 (ADAM17) stimulate the release of ectodomains for a number of transmembrane proteins, such as ACE2 [46]. Therefore, increased ADAM17 activity is thought to be correlated with increased shedding of ACE2 and eventually decreases the possibility of cellular

The expression of ACE2 in the different human tissues was controversial because

ACE2 was newly identified as a major binding site across which SARS-CoV-2 enters human host cells. Recently, many studies were performed to detect the cell types where ACE2 receptor is mainly expressed, which could describe the possible SARS-CoV-2 targets. One study was conducted to address the expression of ACE2 in various natural human tissues, and the analysis of the results regarding age and sex. Highest ACE2 expression levels were detected in the tissues of the small intestine, testicle, thyroid heart, adipose tissues, and kidneys. Esophagus, pancreas, lungs, liver, adrenal gland bladder, and colon were found to express the intermediate level while the lowest expression was found in the stomach nerves, blood vessels, uterus, muscle, spleen, bone marrow, and brain. Regarding lungs, the levels of ACE2 expression were upregulated and downregulated in relation to the immune pattern of men and women respectively [49]. ACE2 also was expressed in certain types of epithelial cells in the airway, such as type II alveolar epithelial cells and ciliated nasal epithelium. Moreover, it was found to be highly co-expressed with the TMPRSS2 in the nasal epithelium, which explains their higher infectivity by COVID-19 [50]. ACE2 is localizing also on the oral cavity mucosa. For now, these results revealed the underlying mechanism that the oral cavity poses a significant potential risk for 2019-nCoV susceptibility, and ACE2 was also expressed in lymphocytes inside the oral mucosa [51]. These findings have reminded us that COVID-19 attacks the lymphocytes and causes lymphopenia, mostly in severe forms of the disease [52]. More importantly, ACE2 also are expressed in endothelial cells [53]. That explains why COVID-19 disease affects multiorgan in the patients [54]. these results indicate that SARS-CoV-2 virus promotes the initiation of endotheliitis in many organs as a direct result of the viral intervention and the inflammatory response of the host. Additionally, the triggering of pyroptosis and apoptosis may have an important role in endothelial cell injury in COVID-19 patients and can account for the weakened systemic microcirculatory performance in various blood vessels and their clinical consequences in COVID-19 patients [55]. This supposition affords justifications for treatments to stabilize the endothelium during viral reproduction, especially by anti-inflammatory cytokines drugs, cholesterol-lowering drugs, and ACE inhibitors [56–59]. This approach can be especially appropriate for weak patients with an earlier endothelial disorder, such as hypertension, diabetes mellitus,

obesity, cardiovascular disease co-morbidities patients [55].

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been studied, and it was found that each variant differs in compatibility with RBD sequence. Specifically, although the majority of genetic variants exhibited high physical similarity. Specifically, the two ACE2 gene alleles (rs143936283 and rs73635825) showed a quite low binding strength for the SARS-CoV-2 spike protein, which could mean a lower possibility of viral binding and possible to infection resistance [80]. It has been observed that the probability of some natural genetic variants of ACE2, particularly those assigned to attach with the SARS-CoV-2 spike protein, may be linked with flexible virus-host interaction, thus likely modifying severity and pathogenicity. A large analysis of the genome data-set was performed and showed that no less than nine human ACE2 variants (E23K, S19P, I21V, N64K, K26R, H378R, T27A, T92I, and Q102P) are prospective to increase predisposition to viral binding, while 17 other variants of ACE2 (that is, E37K, K31R, H34R, N33I, E35K, Y50F, D38V, G326E, N51S, M62V, D355N, K68E, F72V, Y83H, D509Y, G352V, and Q388L) were thought to be protected from viral entry, where they demonstrated a lower binding tendency to SARS-CoV-2 spike protein [81].

In another study, from five separate Italian centers, the authors found that three variants of ACE2 can be specified (p. Gly211Arg, lys26Arg, and p. Asn720Asp). It was noted that these three polymorphisms were recurrently identified in the Italian population rather than the East Asian population. These variants are closely located in the SARS-CoV-2 essential sequence of spike protein binding sites and therefore viral entry and division expected to be modified (for example, Asn720Asp is located on only 4 amino acids of TMPRSS2 cleavage site) [82]. This may tell a partial explanation for the high case mortality rate registered in Italy by comparison to China. Despite ACE2 practically serve as a receptor for coronavirus SARS entry into human host cells, another does not support the correlation between its common gene polymorphisms and receptivity or consequence of SARS [83]. It has also been observed that some ACE2 variants show differential efficacy in stimulating neutrophils, monocytes, natural killer cells (NK), macrophages, and T helper cells, thus

#### **Figure 2.**

*Diagrammatic representation for the renin-angiotensin system (RAS) pathway. As ACE2/Ang 1-7/ Mas-axis and ACE1/Ang-II/ AT1R-axis occur, SARS-CoV-2 inhibition by cleavage of ACE2 by ADAM17 appears. ADAM17: ADAM metallopeptidase domain 17; ARBs: angiotensin receptor blockers; MRAs: mineralocorticoid receptor antagonists [87].*

**183**

**Figure 3.**

*COVID-19) [93].*

*Co-Evolution between New Coronavirus (SARS-CoV-2) and Genetic Diversity…*

**6. TMPRSS2 polymorphism analysis with COVID-19 disease**

may probably either enhance or reduce the inflammatory or "cytokine storm" [84], in addition to stimulating the processing of Ang II, thereby improving or exacerbating vasoconstriction and participating to the improvement or exacerbation of

TMPRSS2 and ACE2 have been associated with SARS-corona (CoV) disease, influenza, and SARS-CoV-2 in facilitating viral entrance into the infected host cell TMPRSS2 considers as an androgen-reactive serine protease enzyme that cleaves SARS-CoV-2 Spike protein, mediating viral activation and entry [88]. Singlenucleotide polymorphisms of TMPRSS2 enzyme have been studied in several diseases such as in breast cancer, the rs2276205 (A > G) with low-frequency allele was correlated with increased patients' endurance [89]. In prostate cancer, the rs12329760 (C > T) of TMPRSS2 has a higher frequency in men with prostate cancer in his family, while ERG gene fusion [90, 91] Rs383510 (T > C) and rs2070788

*A polymorphism and dysregulation of ACE2, and TMPRSS2 in COVID-19 and a suggested model for active compound medicines (e.g., hydroxychloroquine, Camostat mesylate, and E-64D [a protease inhibitor] for* 

*DOI: http://dx.doi.org/10.5772/intechopen.93676*

topical or systemic tissue infection [85, 86] (**Figure 2**).

*Co-Evolution between New Coronavirus (SARS-CoV-2) and Genetic Diversity… DOI: http://dx.doi.org/10.5772/intechopen.93676*

may probably either enhance or reduce the inflammatory or "cytokine storm" [84], in addition to stimulating the processing of Ang II, thereby improving or exacerbating vasoconstriction and participating to the improvement or exacerbation of topical or systemic tissue infection [85, 86] (**Figure 2**).
