The adhesion of the SARS-CoV-2 virus to the ACE2 receptor is observed primarily in the epithelial cell membranes of the cavities of the nose and mouth, the conjunctiva of a person's eye, and the inner ear channel, especially in alveolar cells of type II (AT2), despite the presence of this receptor in other sites of the human body such as Cardiac muscle cells, epithelial cells, ileum, oral and esophageal cells, as well as urothelial cells in the bladder and cells of the proximal tubules of the kidneys (Zou et al., 2020), ACE2/angiotensin system disruption explains specific clinical aspects of SARS-CoV-2 for instance, hypokalemia and vasoconstriction and the development of acute respiratory distress syndrome (Gheblawi et al.,2020). It is noteworthy which the quantity of ACE2 receptor expression in the lung, which is the most important target of the virus, and is considerably lower in the pancreas, cardiovascular gastrointestinal tract, and genitourinary systems (Zou et al., 2020).

         Furthermore, ACE2 plays a crucial role not only in viral infection but also in RAAS by regulating the levels of angiotensin II (ANG-II), The primary source of cardiac complications in COVID-19 appears to be the disruption of the ACE2 receptor mechanism (Yalcin et al.,2021). Additionally, a spike protein of COVID-19 is composed of two distinct regions, namely an S1-containing area and a receptor-binding domain (RBD), the RBD specifically interacts with the angiotensin-converting enzyme 2 (ACE2) receptor, While the S2 region plays a role in the integration of membranes and viral entry, this area is responsible for mediating the fusion of the viral to the cellular membrane (Hoffmann et al., 2020). The process about the fusion of membranes with cells in the host and pathogenic virus particles is initiated via the cells host proteases, namely transmembrane protease serine 2 and B cathepsin (Walls et al.,2020).

          The process of infection occurs in two ways, the delayed path mediated by the endosomal cell and the path mediated by the cell surface, where TMPRSS2 cleaves the viral S protein and thus facilitates the process of virus fusion with the cellular membrane and the integration of nucleic acid within the recipient cell (Jackson et al.,2022). Following the internalization of the virus through ACE2 receptor, proteases enzyme like cathepsin are activated, leading to structural modifications in the spike, these modifications are causes the decrease in endosomal pH (Yang et al., 2020a).

     Furthermore, it is important to take note of the ACE2 receptor as one of the most important receptors for virus attachment and integration into the cell, therefore, the human body contains many other molecules that represent alternative receptors for SARS-CoV-2, including L-SIGN, C-type lectins, and DC-SIGN (Amraei et al., 2021), The role of lectins appears important by distinguishing a wide range of pathogens and ensuring their adhesion between cells, and by distinguishing glycans on the surface of the virion, this contributes to facilitating adhesion and viral entry into the target cell (Wang et al., 2021) . It has been found that cluster of differentiation 147, is the attaching receptor that recognizes the viral protein S as well plays a crucial role in the entry of the virus. This type of receptor was recently linked to the spread of the SARS-CoV-2 infection that causes severe acute respiratory syndrome (Chu et al., 2018).

      Moreover, it has been discovered that CD147 is responsible for the synthesis of various pro-inflammatory cytokines, such as interferon-gamma (INF-), interleukin-6 (IL-6), monocyte chemoattractant protein (MCP-1), and tumor necrosis factor (TNF), also contributes to inflammation (Zhai et al., 2016). In addition to facilitating virus entry and causing a cytokine storm, CD147 has a novel role that contributes to fibroblast activation in COVID-19 pulmonary fibrosis (Wu et al., 2022). The initial stage of viral penetration into cells of interest involves the interaction between the S protein and ACE2. This process is facilitated by the proteolytic breakdown and subsequent fusion of the membranes of the cell and the virus, there is speculation the fact that SARS-CoV-2 could trigger damage to lung tissue (Kuba et al., 2005). One aspect to consider is that upon infecting cells in the lungs, SARS-CoV-2 has been observed to interact through the S1 to ACE2 transmembrane domains, leading to an observed decrease in ACE2 levels (Beyerstedt et al., 2021). The synthesis of Ang II is significantly or comparatively increased, leading to the infiltration of macrophages and subsequent elevation of cytokines and endothelial attachment molecules such as IL-6, MCP1, VCAM-1, selectin E, and various other factors (Li et al., 2018).

     Furthermore, the decrease in ACE2 receptor expression leads to a reduction of the defensive mechanisms against acute pulmonary injury (Imai et al., 2005), Nevertheless, the role of unbound soluble angiotensin-converting enzyme 2 (sACE2) in the process of inflammatory processes and tissue damage may be significant (Haga et al., 2008). Furthermore, the recognition of intracellular signaling by the host cells very significant furin proteases and TMPRSS2 in the S proteins splitting at the S1 / and S2 junctions to help ACE2 linking as well as inside of S2 to trigger the fusion of membranes can be further facilitated by the viruses attaching to ACE2. SARS-CoV 2 additionally adopted an alternative mechanism for infiltrating cells in the host, involving the process of endocytosis followed by fusion mediated by the S protein between the endosome and the virus, the spike protein of the pathogenic virus plays a crucial role in facilitating invasion by controlling the fusion of membranes between the cells in the host, thereby enabling direct transmission of the infection (Papa et al., 2021; Walls et al., 2020).

    The global pandemic that caused by the SARS-CoV-2 has led to significant morbidity and mortality on an international level. In the context of identifying SARS CoV-2 infection at an early stage, host cells employ various pattern recognition receptors (PRRs), the swiftly release of interferon has been shown to be highly efficacious in combating infection with SARS-CoV-2, over time, the virus has developed various strategies to impede the timely release of interferon and undermine the defenses of cells by disrupting multiple stages within interferon-associated signaling pathway, Consequently, certain individuals suffering with COVID-19 exhibited a considerably greater risk to infection with SARS-CoV-2, while others showed either moderate or no symptoms , according to one hypothesis, such variation could be explained by functional changes in innate immune integrity (Lee et al., 2014a ; Liu et al., 2022 ).

    The functions of dendritic cells (DC) encompass the regulation of inflammatory reactions, facilitating the development of tolerance, the infiltration of immune system cells, and the production of antiviral inflammatory mediators, Dendritic cells (DCs) have the potential to play a role in the bodies defenses against COVID-19 (Xiong et al., 2020). This includes facilitating the spread of SARS-CoV-2 to the lymph nodes, as well as contributing to the development of impaired interferon responses and immune responses by T cells in those with the condition. (Alamri et al., 2021).

   Dendritic cells play a crucial role in triggering and modulation of the adaptive immune systems response. These cells have a significant impact on the activation of the body defenses via its IL-17 pathway, primarily by promoting the activation of CD4+ Th17 cell populations by encouraging the monocytes as well as neutrophils (Hunter and Jones, 2015). Plasmacytoid dendritic cells (pDCs) are present in various lung tissues, such as the air passages, parenchyma, as well as the alveolar septa, these are known to generate type I interferon as an immune response to infection by viruses (Li et al., 2019).

    Type I interferon generation is critical to the suppression of infection with SARS CoV-2, as evidenced by the more severe COVID-19 infection in individuals exhibiting auto-antibodies toward IFN or genetic defects of the type I interferon reaction, plasmacytoid dendritic cells represent a unique subset of immune cell types that possess specific abilities in the recognition and controlling of infectious viruses by the strong secretion of type I interferons (IFNs), this illustrates the important role of pDCs in determining the severity of COVID-19 disease (Cervantes-Barragan et al., 2021). Immature DCs first locate and capture the antigen, developing into mature DCs that process and deliver the antigen to class I and class II MHC molecules, activating and differentiating naive T cells into cytotoxic T lymphocytes (CD8+T lymphocytes) and helper T lymphocytes (CD4+T lymphocytes), and ultimately maturing B cells in the lymph node (Yadava and Marsland, 2013).

   Mature dendritic cells regulate the expression of CD80, CD86, and CCR7 (C-C Motif Chemokine Receptor 7) for functional properties, thus, in addition to their high ability to stimulate T lymphocyte responses (Costela-Ruiz et al., 2020).

    Additionally, dendritic cells (DCs) play a significant role in the production IL-6 , This cytokine promotes the triggering of an alternative macrophage pathway, and potentially resulting in the development of acute fibrosis of the lungs (Page et al., 2012). Research upon plasmacytoid dendritic cells (pDCs) in individuals infected via SARS-CoV-2 has demonstrated their capacity to generate type I interferons (IFN I), which play a crucial role in inhibiting the replication of the virus (Cervantes-Barragan et al.,2007).

    Elevated mature DCs in bronchoalveolar lavage may signal the presence of these powerful cells in the lungs and could indicate their response to SARS-CoV-2 infection. DCs, which have moderate expressions of ACE2, are more effector than lymphocytes and less than endothelial/epithelial cells and broadly produce the pro inflammatory cytokines TNF-α and IL-6. (Xiong et al., 2020).

    In addition to the foregoing, macrophage cells are among the main producers of inflammation associated with COVID-19 and excessive inflammation (Bost et al.,2020), and they have a high ability to develop a wide range of membrane receptors that act as sensors for microorganisms and mediating factors, it is soluble and has an important role in specific recognition, signaling, activation, and migration pathways (Guilliams et al., 2018). Moreover, macrophages are recognized to be expert phagocytes when it comes to utilizing complement, Toll-like receptors, Fcs (crystalllizable zone), as well as capture receptors for consuming, effective elimination of pathogens and tissue debris from the body, the oscillation of macrophages is recognized in both cellular as well humoral immune response aspects of the immune system, encompassing both adaptive and innate immunity, and also in antimicrobial defenses and infections Furthermore, macrophages are known to be professional phagocytes in the use of complement, non-actin-like receptors, Toll-like receptors, Fcs (crystallizable zone), and scavenger receptors for ingestion and effective cleansing of the body from harmful agents and tissue debris, it is also known that the macrophage oscillates in the cellular and humoral; Innate and adaptive immunity, antimicrobial defenses, and infections (Gordon and Plüddemann , 2017). It is a double-edged sword, on the one hand, it participates in the mechanisms of tissue repair and homeostasis, and on the other hand, it has the ability to increase tissue damage, by interaction with different cells as well as release enzymes, cytokines and chemokines, and the activation of complement cascades and plasma coagulation (Teuwen et al., 2020). It was classified into two types: pro-inflammatory, denoted by M1, and anti-inflammatory, compensatory, denoted by M2 (Martinez and Gordon, 2014).

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