SARS-CoV-2-Specific Immune Response And The Pathogenesis Of COVID-19 Part 1

Abstract:

The review aims to consolidate research findings on the molecular mechanisms and virulence and pathogenicity characteristics of coronavirus disease (COVID-19) causative agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and their relevance to four typical stages in the development of acute viral infection. These four stages are invasion; primary blockade of antiviral innate immunity; engagement of the virus’s protection mechanisms against the factors of adaptive immunity; and acute, long-term complications of COVID-19. The invasion stage entails the recognition of the spike protein (S) of SARS-CoV-2 target cell receptors, namely, the main receptor (angiotensin-converting enzyme 2, ACE2), its coreceptors, and potential alternative receptors. 

The presence of a diverse repertoire of receptors allows SARS-CoV-2 to infect various types of cells, including those not expressing ACE2. During the second stage, the majority of the polyfunctional structural, non-structural, and extra proteins SARS-CoV-2 synthesizes in infected cells are involved in the primary blockage of antiviral innate immunity. 

A high degree of redundancy and systemic action characterizing these pathogenic factors allows SARS-CoV-2 to overcome antiviral mechanisms at the initial stages of invasion. The third stage includes passive and active protection of the virus from factors of adaptive immunity, overcoming the barrier function at the focus of inflammation, and generalization of SARS-CoV-2 in the body. The fourth stage is associated with the deployment of variants of acute and long-term complications of COVID-19. SARS-CoV-2’s ability to induce autoimmune and autoinflammatory pathways of tissue invasion and development of both immunosuppressive and hyperallergic mechanisms of systemic inflammation is critical at this stage of infection.

Inflammation is a defense response of the body's immune system to external aggression, which manifests itself in symptoms such as local pain, redness, swelling, and heat. When the body is infected or injured, the immune system triggers an inflammatory response to remove pathogens or injure tissue, thereby restoring tissue structure and function. The immune system also releases inflammatory mediators that interact to cause inflammation. These mediators include interleukins, tumor necrosis factors, and interferons, which work by causing inflammation and attracting other immune cells, such as white blood cells, to attack pathogens or rebuild tissue. In daily life, we should pay more attention to the improvement of immunity. Cistanche has a significant effect on improving immunity. The polysaccharides in the meat can regulate the immune response of the human immune system, improve the stress ability of immune cells, and enhance the immune system. Bactericidal effect of immune cells.

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Keywords:

adaptive immunity; autoimmunity; cellular stress; cytokines; interferons; post-COVID-19 syndrome; receptors; SARS-CoV-2; superantigens; systemic inflammation.

1. Introduction

The pandemic associated with the novel Betacoronavirus (β-CoVs or Beta-CoVs), the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that caused the outbreak of the coronavirus disease 2019 (COVID-19), has been a major public health challenge worldwide [1].

On 31 December 2019, the WHO China Country Office was informed of cases of pneumonia of unknown etiology detected in Wuhan (Hubei Province of China), which would later be considered the center for the spread of SARS-CoV-2. 

The current emergence of COVID-19 is already the third severe epidemic caused by β-CoV in humans over the past two decades, after the Severe Acute Respiratory Syndrome (SARS) and the Middle East Respiratory Syndrome (MERS), in 2002 and 2012, respectively [2]. At the same time, SARSCoV-2, having one of the hardest protective outer shells, is expected to be highly resilient in saliva or other body fluids and outside the body and, thus, possess fecal transmission potential [3].

The pathogenesis of COVID-19 is complex, but it can be conceptually described using typical models for the three main pathological processes associated with inflammation— local manifestations of classical general (canonical) inflammation, acute systemic inflammation, and chronic systemic inflammation of low intensity [4]. The probability of the latter process increases with aging, especially in persons with metabolic syndrome, type 2 diabetes mellitus, and some other severe chronic diseases [4,5]

The other side of the research into COVID-19 pathogenesis is the study of selective virulence and pathogenicity factors that are specific to β-CoV viruses in general, or unique to SARS-CoV-2. These factors determine the specificity of the respective disease. Thus, SARS-CoV-2 employs three distinct sets of conventional viral pathogenetic strategies:

(1) Recognition by the virus by cellular receptors, which can be divided into three functional groups:

(a) Receptors that enable the virus to penetrate the target cell. To implement this strategy, viruses strive to increase their binding affinity as well as expand the repertoire of these receptors and their coreceptors [6].

(b) Receptors that transmit to the target cell information useful for the virus (combinations of properties A and B are possible in one receptor).

(c) Cellular receptors which, after recognizing a virus, initiate an antiviral response. In this case, the virus strategy is to inhibit these receptors and their signaling pathways [6].

(2) Suppression of the antiviral response, from both the infected target cells and the immune system of the host organism. This virus strategy can also be subdivided into several components:

(a) Inhibition of early antiviral effects of interferons (IFNs) type 1 (INF-I) and type 3 (IFN-III).

(b) Disruption of universal cellular stress signaling pathways or specific immune pathways.

(c) Protection of the virus from the direct action of antiviral response factors.

(3) The ability of the virus to provoke immune system aggression against its tissues in the form of an autoimmune and autoinflammatory process is a separate strategy for viral survival in the host body.

New information on the presence of a large number of known and unknown SARSCoV-2 receptors allows a more realistic assessment of the efficacy of blocking the major viral receptor (ACE2) in COVID-19 therapy. A deeper insight into the phasing and redundancy in the action of the virus’s pathogenicity factors on the immune system drives a need for a more comprehensive approach to COVID-19 pathogenetic therapy.

Thus, the purpose of this review is to systematize the data on the recently revealed mechanisms of virus penetration into target cells, inhibition of antiviral immune defense, and possible pathways for the development of an autoimmune and autoinflammatory process. The review will attempt to integrate and systematize various and internally contradictory mechanisms of SARS-CoV-2 virulence and pathogenicity.

2. General Characteristics of SARS-CoV-2 Infection

The SARS-CoV-2 virus belongs to the group of enveloped viruses containing a positive single-stranded RNA genome [7]. It is classified into the order Nidovirales, family Coronaviridae, subfamily Coronavirinae, and genus Betacoronavirus [8].

The SARS-CoV-2 genome size is significant and amounts to 29.99 kb [9]. Its organization is similar to that of other CoVs and consists mainly of open reading frames (ORF). About 67% of the SARS-CoV-2 genome is ORF1ab. The latter encodes the synthesis of polyproteins in the infected cell (1a, 1ab). After the synthesis, polyproteins are degraded by two proteases (nsp3 and nsp5) into 16 separate nonstructural proteins (nsp1–16): 11 tsp from the ORF1a segment (nsp1 to nsp11) and 5 from the ORF1b segment (nsp12 to nsp16) [10–12]. The remaining 33% of the SARS-CoV-2 genome is represented by the genes of structural and auxiliary (additional) proteins (ORF3a, ORF3b, ORF6, ORF7a, ORF7b, ORF8, ORF9b, ORF10). ORFs are distributed between structural genes and, accordingly, encode viral proteins: orf3a, orf3b, orf6, orf7a, orf7b, orf8, orf9b, orf10 [12–21].

The four structural proteins of SARS-CoV-2—(1) spike (S) glycoprotein, (2) small envelope glycoprotein (E), (3) membrane glycoprotein (M), and (4) nucleocapsid protein (N)—are responsible for viral replication and structuring, virus binding with cellular receptors (S), as well as for the pathogenicity of the virus [14,22,23] (Figure 1).

Once assembled, viruses are transported by vesicles to the host cell membrane and released by exocytosis. When being transported to the cell surface, S-protein allows the infected and healthy cells to be fused, resulting in the formation of large multinucleated cells which spread the virus in the host organism [24].

A common feature of all three well-known β-CoVs, namely SARS-CoV-1 (the causative agent of SARS), MERS-CoV, and SARS-CoV-2, is that they can replicate in the lower respiratory tract and cause fatal pneumonia [2]. The likelihood of death increases sharply with the development of acute respiratory distress syndrome (ARDS) [25]. In this case, viral expansion in the body, hypoxia, entry of tissue decay products into the bloodstream, pathological hyperactivation of T cells and macrophages, and intravascular activation of leukocytes, complement systems, and hemostasis lead to a range of resuscitation syndromes pathogenetically associated with systemic inflammation [4,25,26].

The SARS-CoV-2 virus is significantly less lethal than SARS-CoV-1 or MERS-CoV, but it is transmitted much easier and faster [27,28]. The long incubation period and the presence of asymptomatic variants of COVID-19, as well as the high level of contagiousness and transmissibility, make the identification, tracking, and elimination of this disease challenging [27,28].

The main route of infection for SARS-CoV-2 is through respiratory droplets, but contact with an infected surface can be also important [29]. The incubation period of COVID-19 is from three to 14 days and depends on the immune status [30]. The typical symptoms of COVID-19 include fatigue, fever, dry cough, malaise, sore throat, loss of taste and/or smell, and in some cases, shortness of breath, diarrhea, and characteristic signs of viral pneumonia [31].

A special stratum of viruses is the inhibition of the signaling pathways of receptors responsible for triggering antiviral immunity. Primarily, these are pattern recognition receptors (PRRs), which recognize conserved molecular structures known as a pathogen or injury-associated molecular patterns (PAMP and DAMP). PAMPs are associated with microbial pathogens, while DAMPs are associated with the host cell components that are released during cell damage or death. The main PRR families for the recognition of viral RNA in endosomes are Toll-like receptors (TLR), while cytoplasmic viral RNA is recognized by RIG-I-like receptors (RLR) [32]. 

Activation of these receptors leads to the activation of an antiviral innate immune response, primarily associated with the production of IFNs. Scavenger receptors (SR) are a special group of molecules capable of non-strictly specific interaction with viruses [33]. This is a large group of receptors at the intersection of immunity and metabolism. They are predominantly expressed on stromal macrophages and dendritic cells [34]. Also, SR can act as cofactors of PRRs, including TLRs, in the recognition and neutralization of viruses by cells of innate immunity, but, in some cases, they can act as a gateway for viruses (including SARS-CoV-2) to infect cells [35].

Additionally, a common pattern in the pathogenicity of viruses, including CoVs, is their ability to suppress the production and function of IFNs of type 1 (multiple forms of IFN-α - 13 factors, IFN-β, IFN-ε, IFN-κ, IFN-ω), and type 3 (IFN-λ1–4), triggering hundreds (> 300) of IFN-stimulated genes (ISG) [36–40].

The impact of viruses on the activation mechanisms of cellular stress in immunocompetent cells is also significant, as it causes polyclonal activation and apoptosis of lymphocytes (primarily T cells), pathological activation of macrophages, and immunosuppression [41].

RNA viruses such as CoVs exhibit a much higher evolutionary rate than DNA viruses due to their high susceptibility to replication errors mediated by RNA polymerase or reverse transcriptase, and due to the significant size of the viral population with a higher replication rate [42,43]. Currently, the identification of all SARS-CoV-2 mutations and their connections with pathological changes is almost impossible, mainly because there are asymptomatic patients [24]. 

However, a global analysis of the known genomic epidemiology of SARSCoV-2 is available in the public domain [44]. Omicron is characterized by a large number of mutations in the spike protein (more than 30), as well as new mutations in the nsp12 and nsp14 proteins [45–47]. Omicron is more transmissible than the Europe-wide spread variant of Delta SARS-CoV-2; it is capable of significant immune evasion (including from the currently used vaccines) and spreads faster than any previous variants of the virus [48–54].

Overall, the genome of the current epidemic SARS-CoV-2 virus has undergone significant changes compared to the reference genome obtained in January 2020. The most significant mutations that significantly alter virulence and pathogenicity occur in the Sprotein [9]. Harmful variations in nsp12, in the N-protein, were also described [55,56]. The spread of new mutations in the S-protein can potentially reduce the effectiveness of the immune response to vaccines [57]. A systematic assessment of all 3686 possible future mutations in the S-protein domain that binds cell receptors shows that future mutations will most likely make SARS-CoV-2 even more infectious [58].

3. SARS-CoV-2 Receptors

Coronaviruses bind to host receptors through their spike S-glycoproteins, which mediate membrane fusion and viral penetration [59]. The main receptor for SARS-CoV-2 is membrane angiotensin-converting enzyme 2 (ACE2) [60]. There are two isoforms of ACE2, and one of them cannot bind to SARS-CoV-2 [61–63].

S-protein forms trimers on the surface of the virus [64]. After RBD-receptor interaction, the S protein undergoes proteolytic cleavage at the N-terminal S1 subunit and the C-terminal S2 subunit of host proteases. This partial proteolysis is catalyzed by the transmembrane protease serine 2 (TMPRSS2) and can be activated by furin or furin-like proteases (e.g., plasmin) or after endocytosis by cathepsins B/L [64]. The receptor-binding domain (RBD) of the S1 subunit directly interacts with the ACE2 (Figure 2). However, in the S-protein trimer, only one of the three RBDs can be turned upward in a receptor-accessible conformation. 

At the same time, SARS-CoV-2 is in a state of low activity for binding to ACE2 for a considerable time, since RBD is shielded by the carbohydrate component of the S-glycoprotein, which protects the virus from antibodies [65]. Therefore, RBD undergoes a hinge conformational movement that temporarily obscures or exposes receptor-binding determinants [66]. This SARS-CoV-2 property limits the ability to neutralize the virus with antibodies and drugs targeting RBD binding.

Figure 2. The receptor function of SARS-CoV-2 S-protein. Proprotein convertases (e.g., furin) act after the virus attaches to ACE2. The presence of a furin cleavage site at the S1/S2 border in SARS-CoV-2 probably reduces the dependence on target cell proteases [65]. Cell surface proteases (e.g., TMPRSS2) catalyze the cleavage of S1 and its separation from the S2 domain [64]. Acid lysosomal proteases act after viral endocytosis, in the lysosomal pathway of transformation of the virus in endosomes. Moreover, due to the complexity of in vivo processes and infection of various cell types with SARS-CoV-2, other host proteases can potentially participate in similar cleavage of the SARS-CoV-2 S protein [15].

Thus, after attachment to the receptor, proteolytic processing activates the S-protein and makes possible the fusion of the membranes of the virus and the target cell, followed by the release of viral RNA into the cytoplasm of the cell. 

In this case, the distal S1 subunit plays a role in the recognition and binding of the receptor, while the anchored S2 subunit mediates the fusion of the membranes of the virus and the host cell [67]. SARS-CoV-1 also enters cells by endosomal pathways, where the S-protein is activated for the fusion of the viral and endosomal membranes by trypsin-like proteases (e.g., cathepsin B) in an acidic endosomal environment [68]. This path is quite possible for SARS-CoV-2 [69,70]. Many coreceptors acting synergistically with ACE2 can activate the endosomal pathway [65].

Due to differences in the spectrum of ACE2 genetic variants, ACE2 receptors feature different degrees of binding affinity for the S-protein. Several ACE2 variations can form high-affinity double mutant complexes with S-protein, which can influence an individual’s susceptibility to infection [71]. 

Moreover, hundreds of variants in the RBD domain have been found, of which the mutant type V367F constantly circulating across the world exhibits a greater binding affinity for ACE2 [72]. The presence of numerous mutations in the S-protein also indicates the ability of the spike protein to acquire new properties of ligand specificity [73]. In particular, the importance of searching for alternative ACE2 receptors to SARS-CoV-2 is highlighted by the reports, suggesting that bone marrow cells that do not express ACE2 could be infected with this virus [74].

Recently, several membrane proteins that can act as ACE2 cofactors or alternative receptors have been discovered (Table 1). Thus, S-glycoprotein can interact with receptors not only through its protein part but also by binding to lectin receptors with its carbohydrate component (N-glycans of the S1 subunit, containing oligomannose and complex sugars that protect the virus from antibodies) [15,75,76]. Lectin-like S1 sites, in turn, bind to heparin, which can affect and even prevent viral invasion [77]. On the contrary, binding of lectin-like S1 sites to the target cell glycocalyx can facilitate invasion, since the glycocalyx contains coreceptor sugars for binding SARS-CoV-2, namely, O-acetylated sialic acids [78] and heparan sulfate [79]. 

It was shown that heparan sulfate could enhance the penetration of many types of viruses [80]. The interaction of the lectin-like S1 domain with the glycocalyx of target cells may have a cofactor significance for the ACE2 receptor function during cell infection with SARS-CoV-2 [79,81]. The possibility of SARS-CoV-2 S protein binding to the integrin receptors of the RGD motif (Arg-Gly-Asp) in the RBD S1 domain is also discussed [82]. At the same time, it is not always clear whether these interactions contribute to viral invasion or virus neutralization.

Many RNA viruses use extracellular vesicles (exosomes and exosomes) for translocation into new host cells [107,108]. These vesicles allow viruses to infect cells via virus-specific receptors as well as in an independent manner. It was suggested that the cellular transport pathway associated with the release of SARS-CoV-2-loaded extracellular vesicles might represent potential mechanisms for the relapse of COVID-19 infection [109]. In particular, exosomes expressing ACE2, CD9, and other tetraspanins on their surface can be mediators of COVID-19 infection [110]. At the same time, exosomes can transfer viral particles from infected cells to healthy ones and modulate the host’s immune responses and thus can be exploited for the therapy of COVID-19 [111].

Overall, the entry of SARS-CoV-2 into host cells is a complex, multifactorial process. Even the main mechanism associated with ACE2 requires the involvement of many auxiliary molecules in the process—proteinases, coreceptors, and activators of their expression. The presence of coreceptors, in particular, enables SARS-CoV-2 to infect cells with low ACE2 expression on membranes. Simultaneously, there is increasing evidence of the availability of alternative ACE2 pathways for target cell infection [100]. The variety of mechanisms of SARS-CoV-2 tropism in human tissues can explain its high contagiousness, as well as viral invasion of internal organs during the progression of COVID-19 (Table 1).

However, the preliminary data on the role of CD147 as an ACE2-independent receptor for SARS-CoV-2 [89] were not fully confirmed [90]. The CD147 mechanism appears to be more complex and indirect and associated with the regulation of ACE2 membrane expression [90]. At the same time, it was shown that the scavenger receptor SR-B1, which recognizes high-density lipoproteins (HDL), promotes SARS-CoV-2 penetration in an ACE2-dependent way [35]. The S1 subunit of the virus binds to cholesterol and HDL components, which increases viral uptake. 

Because SR-B1 interacts with these receptors, SARS-CoV-2 was found to enter cells expressing ACE2 more easily when SR-B1 was expressed. SR-B1 has been reported to co-express with ACE2 in human lung tissue and various extrapulmonary tissues [35]. The fact that SR-B1 has numerous functions, including being a viral scavenger, immunomodulator, and virus penetration intermediate [101], explains its involvement in COVID-19.

The potential ability of the C-type lectin CD209L (L-SIGN) to act as an independent SARS-CoV-1 receptor on target cells was also described [112,113]. In this regard, the attention of researchers was drawn to the report on the identification of CD209L and the related protein CD209 (DC-SIGN) as receptors capable of mediating the penetration of SARS-CoV-2 into human cells [97]. The receptors CD209L and CD209 interact with the ligand-specific (for ACE2) site of the S-protein in RBD. 

In addition, CD209L also interacts at the cell membrane with ACE2, suggesting a role for CD209L and ACE2 heterodimerization in SARS-CoV-2 penetration and infection in cell types where both are present, such as human endothelial cells. This determines both ACE2-independent and ACE2-dependent roles of CD209L in SARS-CoV-2 entry and infection. CD209L and CD209 were shown to serve as alternative receptors for SARS-CoV-2 in cell types where ACE2 is low or absent. Meanwhile, the capture of CD209 viruses in macrophages and dendritic cells can lead not to the infection of these cells but the utilization of viral particles, whereas in other cases, it leads to the infection of T-lymphocytes in contact with macrophages [99].

Patients with a severe case of COVID-19 demonstrate significant complement activation in the lungs, skin, and serum [114]. Activation of the complement system in COVID-19 occurs in a variety of mechanisms, most of which are linked to the activation of hemostasis systems and kallikrein-kinins, as well as with damage to the vascular endothelium and other tissues [115,116]. SARS-CoV-2, on the other hand, has been demonstrated to activate complement via the lectin pathway [117].

There is evidence of the ability of the SARS-CoV-2 S protein to bind to membrane PRRs, including TLRs, especially the TLR4 [100,118,119]. It is assumed that S-protein binds to TLR4 and activates TLR4 signaling to increase the expression of ACE2 on the cell surface, thereby facilitating the penetration of SARS-CoV-2 into type II alveolates [120]. This contributes to cell destruction, disruption of surfactant production, and ARDS development.

It is assumed that myocarditis caused by SARS-CoV-2 may be associated with TLR4 activation and subsequent hyperactivation of the innate immune response [120]. The native S-protein SARS-CoV-2 binds to TLR1 and TLR6, though with lower binding energy than TLR4 [119] according to molecular docking studies. It is important to remember that TLRs can form intricate complexes with other receptors in the presence of ligands, including SR, integrins, tetraspanins, and Fc receptors (FcR) [33,34]. This scenario precludes simultaneous recognition of not just unique and characteristic viral antigens but also other alterations in the organism’s genetic and phenotypic homeostasis. These changes, including the accumulation of endogenous PRR ligands, particularly DAMP, in the blood and other tissues, grow like an avalanche as the viral infection progresses.

A single-stranded SARS-CoV-2 RNA can bind to TLR7 and TLR8, while double-stranded virus RNA (temporarily generated during single-stranded virus RNA replication) can bind to TLR3 in macrophages and dendritic cells [121]. These interactions (through TLRs in endosomes) induce IFN-I responses and the generation of various cytokines, resulting in viral infection suppression [122]. 

However, PRRs of the RLR family, primarily RIG-I (retinoic acid-inducible gene I) and MDA5 recognize SARS-CoV-2 RNA in the cytoplasm of numerous cell types, inducing IFN-dependent stress in infected cells [37,123]. These receptors interact with viral double-stranded RNA appearing during RNA replication. They have a caspase activation and recruitment domain (CARD) that activates various apoptotic and inflammatory signaling pathways. RLR signaling pathways are associated with antiviral signaling in the mitochondria (mitochondrial antiviral-signaling protein, MAVS). MAVS leads to the production of several multifunctional protein complexes after RLR-dependent activation. On the ER and mitochondrial membranes, RLR-MAVS interacts with STING (stimulator of interferon genes) and TRAF3 (TNFR-associated factor 3), activating TBK1 (TANK-binding kinase 1) and IKK (inhibitor of B kinase epsilon) kinases [114,124]. 

The transcription factors IRF3 (interferon regulatory factor 3) and NF-κB (nuclear factor-kappa B) are then activated by these kinases [124–126]. STING is a critical PRR in this scenario, as it combines responses to viral RNA and DNA, as well as intracellular DAMPs (endogenous DNA trapped in the cytosol) [127,128]. IKK and TBK1 are also involved in the TLR3 (activates TRAF3) and TLR4 (through MyD88) signaling pathways [129,130]. The signaling pathways of RLR, TLR, cytokine receptors, and other signaling structures that induce the production of interferons (especially through the activation of IRF3) and the development of cellular stress in general (especially through the activation of the multifunctional NF-κB) can thus be intertwined during a viral invasion.

In patients with COVID-19, the RLR/MAVS-mediated signaling pathway not only plays a role in the antiviral response, but its failure can also lead to autoimmune disorders and trigger a cytokine storm [37]. Furthermore, SARS-direct CoV-2’s impact on the nod-like-receptor (NLR) and secondary changes in intracellular homeostasis induce viral nonspecific cellular stress pathways in diverse cells, such as NF-κB activation and NLRP3 inflammasome assembly [131,132]. 

Inflammasomes, in turn, increase the synthesis of IL-1β and IL-18, as well as pyroptosis, a type of planned necrosis in which a substantial amount of DAMP escapes the cell [133]. Inflammasome development can have both protective and pathogenic implications depending on the circumstances. COVID-19 dysfunction can result in not only harm to host tissues but also the development of systemic inflammation [4]. Other cellular stress pathways that are influenced by SARS-CoV-2 include:

• Oxidative stress [134,135];

• Autophagy and lysosomal stress [136,137];

• Ubiquitination of proteins; this process is important for the regulation of function and proteolysis of many intracellular proteins [138];

• Mitochondrial stress, in particular, is dependent on the RLR/MAVS signaling pathway [139];

• Endoplasmic reticulum (ER) stress [140];

• Expression of non-coding, regulatory RNAs [141–144];

• Expression of heat shock proteins (HSP) [81,145];

• Cell response to the DNA damage [146,147];

• The formation of a pro-inflammatory cell secretory phenotype, which can manifest itself as a cytokine storm syndrome when generalized to the whole organism.

Thus, the recognition of SARS-CoV-2 target cells and vice versa—the recognition of the pathogen by the sensors of the cell’s antiviral defense is the first stage of virus invasion. In this scenario, it is not only the virus’s main receptor (ACE2) and its coreceptors that are engaged but also the virus’s alternate receptors. This enables SARS-CoV-2 to infect a large range of target cells in a variety of human organs. Several universal and viral invasion-specific cellular stress signaling pathways are triggered during virus penetration into target cells. 

Furthermore, at the level of individual cells and the organism as a whole, an escalation of the mutual opposition of immune systems, principally IFN-dependent, and the already developed system (virus and recruited proteins) of the virus’s vital factors develop. The outcome of this battle will influence how the infection develops and progresses.

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