**2. Pathways of cellular infection by SARS-CoV-2**

SARS-CoV-1 and SARS-CoV-2 connect to a similar receptor on the surface of human cells, known as angiotensin-converting enzyme 2 (ACE2) [41]. This complex particularly includes the receptor-binding domain (RBD) positioned within the virus spike protein (S protein). However, recent laboratory studies have revealed that unlike SARS-CoV-1, the SARS-CoV-2 RBD favors creating a greater binding capacity (i.e. 1204 versus 998 Å) [41, 42]. The SARS-CoV-2 infects and enters the infected cell by binding the viral spike protein with ACE2 of the host cell through the RBD. Even so, the splitting of spike protein needs to be done by human protease, where S protein subunits (S1 and S2) are broken apart from each other, with the last domain undergoes considerable structural modifications necessary to bind with the cell membrane of the host cell [43]. The transmembrane serine

#### **Figure 1.**

*Genetic Variation*

getting a disease or infection [7, 8].

survival [1–4]. Determining the host genetic implications in the risk of the epidemic and its severity remains the biggest obstacle to the infectious disease research progression [5, 6]. Because of the large size of the samples required by quantitative genetic studies, the definition of disease resistance based on individual mortality must be changed because it is easy in any case to know if the subjects' mortality was happening due to the exposition to infectious diseases or not. But, this is not true in the case of survival because it is multisided, and it may depend not only on an individual's resistance to infectious agents but also on his ability to survive after

Obviously, interest has increased in the infectivity genetic regulation, which can be described as the capability of a pathogen to infect an individual upon contact. Comprehension of the genetic regulation of infectivity is especially relevant if there are contrary genomic associations between these traits and elements of tolerance or resistance [9–11]. Such unfavorable genetic associations could be arising if subjects with much genetic survival not only come over with infection but also have a tendency to shed more pathogens [12]. Endurance and resistance infectivity may be controlled by several gene sets with variable contributions, both in degree and direction for survival [7, 13]. Despite this, no study has investigated these three traits at the same time. It is worth noting that plenty of quantitative genetic studies revealed variation in genetic resistance [2, 14–16], however, only a few studies showed a genetic difference in disease survival [7, 8]. In the context of infectious diseases, genomic selection may definitely restrict the spread of the disease by implementing

Almost two decades after the outset of the Severe Acute Respiratory Syndrome (SARS), produced by a beta coronavirus, recently called SARS-CoV-1, the world was surprised by the emergence of a more virulent and infectious new virus in late 2019. This virus soon spread to almost all parts of the world and quickly reached the epidemic disease state [17]. The new coronavirus 2019 (COVID-19) outbreak originated from the SARS-CoV-2 virus suddenly became a major public health threat. COVID-19 is characterized by different types of clinical characterizations: affected patients can be asymptomatic, symptomatic with mild respiratory symptoms, or manifest severe pneumonia [18–21]. It is noted that these estimations are variable and began to approach accuracy as more cases are described, examined, and analyzed. Curiously enough, there is a clear difference in these estimations among different countries, worthy to mention that, the differences in the severity of the virus were recorded between the sexes and different age categories [18, 20, 22]. The infected cases have increased drastically [23]. Transmission from one person to another has been confirmed [24]. The virus was discovered in Bronchoalveolar lavage (BAL) [22], saliva and nasopharyngeal swabs [25], sputum [26], and throat [27, 28]. Even though the number of patients with COVID-19 was asymptomatic or mildly symptomatic still indecisive until now, but some studies have suggested that

Among the most debatable characteristics in the clinical course and pathogenesis of COVID-19 is the heterogeneous hazard in the development to the acute form. Some significant clinical factors have been specified as severe disease predictors in different populations around the world, essentially include old age, male sex, obesity, and presence of multiple co-morbidities, such as diabetes mellitus, hypertension (HTN), cardiovascular disease, and impaired liver and renal function [20, 31–33]. In fact, some patients continue completely without symptoms until the final viral shedding, however, others experience a highly aggressive form of the disease [34–39]. These severe cases in the clinical picture of COVID-19 firmly propose that other co-factors may have a vital role in modifying disease development and progression. The suppressed immune response in the elders, co-morbidities,

a mechanism for determining high-risk people of infection [1].

the percentage is between 40 and 80% [29, 30].

**178**

*Illustration of the COVID-19 virus spike protein. Across ACE-2 receptors, the spike invades the cell. Afterward, the spike is cleaved by the host cell proteases, membrane protease 2 (TMPRSS2), and furin, which results in COVID-19 infection activation [48].*

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