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

4. Pathogenicity Factors of SARS-CoV-2 Overcoming the IFN-Response at the Initial Stages of Viral Invasion

The cell’s response to infection is initiated by viral PAMPs, which are recognized by PRR, followed by activation of downstream signaling molecules such as adapter proteins MAVS and MyD88, kinases TBK1, IKK, transcription factors IRF3, NF-κB, activator protein 1 (AP-1), and others, which results in high IFN-I-III production and pro-inflammatory cellular stress in general. 

This is referred to as primary IFN production. The result of the PRR’s initial stimulation of cells is a positive feedback loop in the form of the interferon response. IFN-I-III activates signaling pathways involving the kinases Tyk2 (tyrosine kinase 2) and Jak1 (Janus kinase 1), which are directly linked to the intracellular domains of two IFN-I (IFNAR1/IFNAR2) and IFN-III (IL-10R2/IFNLR1) chains. The ISGF3 transcription factor complex (STAT1-STAT2-IRF9) is thus activated and penetrates the cell nucleus, activating the ISG genes [148]. A recent study demonstrated the presence of STAT1-independent mechanisms of ISG promoter activation (through binding to ISRE—interferon-stimulated response element), through the transcription factor complexes STAT2-IRF9 and STAT6- STAT2-IRF9, which are also linked to the function of IFN receptors (IFN-R) [149].

In the human immune system, tyrosine kinases are involved in multiple immune-related physiological processes. For example, in the activation process of B cells and T cells, the activation of tyrosine kinases is necessary; in tumor immunity, tyrosine kinases also play an important role. In addition, tyrosine kinases are also involved in the immune activity of other cells, such as macrophages, natural killer cells, dendritic cells, etc. Therefore, tyrosine kinase plays a vital role in the human immune system and plays an irreplaceable role in maintaining the health of the body and preventing diseases. Not only that, but we should also pay attention to improving immunity in our daily life. This is as important as it is. Cistanche can enhance immunity, because Cistanche contains a variety of biologically active components, such as polysaccharides, two mushrooms, and Huang Li. etc. These ingredients can stimulate various cells of the immune system and increase their immune activity.

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Furthermore, ISG expression products (OAS, IFITM, and others) protect cells from coronavirus infection by degrading viral RNA and reducing virus penetration [150]. Moreover, IFN-IRs are expressed almost everywhere, but IFN-III-R is only found in cells that line the epithelial barrier [151]. 

In general, both the production of IFN-I-III and the subsequent transmission of secondary signals by them for the development of antiviral cellular stress are critical for controlling the development of the early stage of coronavirus infection. Overcoming the IFN-dependent processes of innate immunity is a common viral invasion strategy, and COVID-19 is no exception. Inhibition of these processes, in turn, is a prerequisite for viral invasion. The main points of inhibition include:

(1) Inhibition of the formation and function of PRRs that recognize SARS-CoV-2 RNA.

(A) Non-structural proteins nsp14 (N-7-methyltransferase) and nsp16 (2-O0 -methyl transferase) β-CoV can modify viral RNA to prevent it from being recognized by PRR and IFIT1 (interferon-induced protein with tetratricopeptide repeats 1, which inhibits viral replication and translation initiation) [152,153]. The nsp16 factor, in conjunction with nsp10, methylates the viral mRNA’s 50 ends to mimic the host’s mRNA [154,155].

(B) Factor nsp1 blocks several cell proteins, including antiviral PRRs, from being synthesized on ribosomes, while N and M proteins bind to and inhibit RIG-I. (Table 2).

(2) Inhibition of IRF3 activation and translocation into the cell nucleus or cleavage, which initiates IFN-I-III production. Many of the SARS-CoV-2 proteins (nsp1, nsp3, nsp5, nsp6, nsp9, nsp13, nsp14, nsp15, orf3b, orf6, orf9b, N, and M) can block a variety of signaling pathways, including RLR/MAVS/TRAF3/(IKK and TBK1)/(IRF3, NF-κB)/ (Figure 3).

(3) Inhibition of IFNs synthesis on ribosomes (nsp1, Table 2).

(4) Inhibition of transmembrane transport of IFNs (nsp8, nsp9) (Table 2, Figure 3).

(5) Inhibition of IFNAR1–IFN-IR chain (orf3a), inhibition of Tyk2 kinase associated with IFN-R (nsp1) (Table 2, Figure 4) [156–220].

(6) Direct inhibition of ISG expression by blocking the activation and translocation into the nucleus of the ISGF3 complex, which initiates ISG transcription. For example, nsp1, nsp3, nsp6, nsp13, orf3a, orf6, orf7a, orf7b, orf8, and M (Table 2) have pathogenic capabilities for blocking several signaling pathways, including IFN-I-III/IFN-R (Tyk2, Jak1)/ISGF3 (STAT1, STAT2, IRF9)/ISG/antiviral response, cellular stress (Figure 4).

Figure 4. Inhibition of the key IFN-I-III signaling pathways by SARS-CoV-2. Orf8 blocks the attachment of the ISGF3 complex to the ISRE site on the promoters of antiviral response genes—ISG. Additionally, Figure 3 shows the possible inhibitory effect of autoantibodies that bind IFNs. Therefore, the presence of neutralizing autoantibodies to IFN-I is a predictor of critical COVID-19 pneumonia [216–219]. IFN receptors and signaling routes for activation of ISG genes are colored red, IFN receptors and signaling pathways for activation of ISG genes are colored blue and cyan, and ISG gene products are colored green. The arrows point in the direction of the impacts of the respective molecular structures’ actions.

In general, the pathogenicity factors of SARS-CoV-2 can inhibit all the main stages of IFN protection with a high degree of redundancy due to both the large number of factors involved in this inhibition and their multi-functionality. The synthesis of interferons (IFNs) during viral infection is avalanche-like. As a result, disrupting all developmental phases of the IFN response at the same time is an effective multilateral mechanism that suppresses the host’s antiviral response synergistically [176]. Among the 27–28 viral proteins found in SARS-CoV-2, nsp1 [155] and orf6 [150] were thought to have the greatest impact on both primary IFN-I-III production and signaling to ISG. However, in SARS-CoV-2 infection, nsp13, nsp14, nsp15, and orf6 have also been demonstrated to be powerful interferon antagonists [150]. Thus, it is probable that the repertoire of dominant IFN inhibitors varies depending on the cell type and state of function. These processes work together to allow SARS-CoV-2 to reproduce in a variety of cell types while also overcoming innate and adaptive immunity’s antiviral capabilities.

Consequently, the complex of SARS-CoV-2 pathogenicity factors aims to prevent IFN-I-III antiviral activity from being formed and implemented [221]. As a result, genetic defects in the generation of IFNs or the presence of autoantibodies that disrupt IFN function are evident risk factors for the severe course of COVID-19 [222]. Suppression of IFN-I-III activity at the outset of the disease is critical for viral invasion, as IFN-I-III has the greatest antiviral effectiveness during this time. Overproduction of IFNs may also play a deleterious effect in the latter and more severe stages of COVID-19, as it is implicated in the pathophysiology of the cytokine storm phenomenon and associated systemic inflammation [4]. 

As a result, a severe form of COVID-19 with the development of ARDS and an increased level of pro-inflammatory cytokines in plasma, such as IL-1β, IL-6, TNF-α, chemokines—CXCL10 (IP-10), CCL2 (MCP-1), and CCL3 (MIP-1α), is characterized by low IFN-I levels in the blood at an early stage and increased IFN-I levels at a late stage of COVID-19 [197]. It is important to remember that IFN- λ1, which is produced due to the activation of RIGMDA-5, TLR3 receptors, and RIG-I has the most significant protective role in the infection of respiratory epithelial cells with SARS-CoV-2 [223]. It is important to remember that IFN-λ1, which is produced due to the activation of RIG-I, MDA-5, and TLR3 receptors, has the most significant protective role at the beginning of the SARS-CoV-2 infection of respiratory epithelial cells [223]. When compared to patients with a milder form of COVID-19, IFN-I, and IFN-λ2 expression appears to be much higher (particularly in the lower respiratory tract) in patients with a severe course of the disease [223].

These findings back up the theory that IFNs have an ambiguous role in the airways. Effective initiation of IFN production in the upper respiratory tract can lead to faster virus clearance and possibly limit virus transmission to the lower respiratory tract. When the virus escapes immune control in the upper respiratory system, however, the generation of IFNs, which are considerably boosted in the lungs, is likely to contribute to the cytokine storm and tissue damage that occurs during COVID-19 progression to the critical stage. IFN produced the lowest (weakest) ISG response in the above example, but it significantly increased the surface expression of ACE2, which is crucial for SARS-CoV-2 penetration [224]. IFN-γ, secreted mainly by type 1 T-helper cells (Th1), is a key activator of type 1 proinflammatory macrophages (M1). The antiviral immune response of these cells is linked to the risk of photogenic substances damaging their tissues [4]. 

At the same time, IFN-I-III is primarily produced by virus-infected cells, whereas IFN- is primarily produced by lymphocytes activated by secondary immune factors but not infected by the virus. Therefore, the imbalance between the activation and limiting mechanisms of cellular stress in immunocytes induced by SARS-CoV-2 contributes to the disruption of both the innate and adaptive antiviral responses.

5. Dysfunction of the Adaptive Antiviral Response. The Alleged Role of the Autoimmune Process in the Pathogenesis of COVID-19

5.1. The Main Features of Immune Response Development and Its Dysfunctions in COVID-19

Possible variants of the strategy employed by viruses for evading immune response factors are screening for antigenic structures, induction of polyclonal lymphocyte activation, autoimmune response induction, blocking of the interaction between major histocompatibility complex (MHC) proteins on antigen-presenting cells (APC) and T-cell receptor (TCR), dysregulation of the cytokine network, an imbalance between the individual vectors of the immune response: i1 (Th1, macrophages–M1, normal killer cells–NK, cytotoxic T-lymphocytes–CTL), i2 (Th2, M2a, eosinophils, mast cells), i3 (Th17, M2b, neutrophils), i-reg (Treg, M2c) [225–227]. The implementation of these strategies can lead not only to an increase in the viral invasion but also to the development of secondary (bacterial and fungal) infections, and local and systemic damage to tissues by variants of autoinflammatory and autoimmune reactions.

Five SARS-CoV-2 nbsp (nsp7, nsp8, nsp9, nsp12, and nsp13) and structural proteins (S, E, M, and N) were found to include conserved peptides whose immunogenicity is determined by their ability to bind to MHC-I/II proteins [228].

RBD-specific antibodies identified in persons recovering from COVID-19 have been shown to protect against reinfection with SARS-CoV-2 [229]. Patients infected with SARSCoV-2, on the other hand, show an early conversion of antitelogenesis from immunoglobulins of the IgM class to IgG and, to a lesser extent, IgA (7–14 days after the onset of symptoms) [225,229].

Anti-S-protein immunoglobulins produced for vaccines have also been shown to play a protective role in the prevention and reduction of COVID-19’s critical consequences [230,231]. The existence of IgG antibodies to S or N protein was related to a considerable reduction in the risk of SARS-CoV-2 re-infection in the next 6 months [232]. In general, only a few cases of reinfection have been reported over the world, implying long-term protective immunity [233]. 

In Qatar, only 243 people (0.18 percent) out of 133,266 laboratory-confirmed cases of SARS-CoV-2 had at least one subsequent positive result of detecting the RNA virus 45–129 days after the initial verification of COVID-19, and clinical evidence of reinfection was only established in 54 cases (22.2 percent) [234]. Meanwhile, several studies have shown that SARS-CoV-2 can survive for lengthy periods in the lack of antiviral IgG and that recovery from COVID-19 can occur in the absence of antiviral antibodies [235].

Antibody-dependent enhancement (ADE) is a phenomenon in which an attachment to antibodies does not destroy the virus, but rather facilitates its entry into the cell, promoting viral reproduction and virulence [225]. After attachment to the virus, antibodies against the S-protein mediate ADE via binding to FcR on different cells in the case of MERS-CoV and SARS-CoV-1 [236,237]. That said some researchers suggest that ADE can occur in SARS-CoV-2 infection [238–240].

Many SARS-CoV-2 proteins, including naps, S, M, N, and orf3a, can serve as a source of Ag for antigen-specific CTL presentation (MHC-I + Ag) [241]. In addition, SARS-CoV-2 infection triggers Th1 development via involving MHC-II at the APC [242,243], which is accompanied by an accumulation of i1-response products in the blood, such as IFN-γ (primary producers–Th1), TNF-α, and neopterin (products M1) [244]. SARS-CoV-2 infects alveolar macrophages in the lungs, prompting them to produce chemoattractants for Th1. Th1 cells then release IFN-γ, which further activates resident and monocyte-recruited macrophages’ antiviral and proinflammatory activities [245]. As a result, a positive feedback loop develops, resulting in prolonged alveolar inflammation. 

Inadequately high M1 activation can cause changes in the COVID-19 inflammation zone in the lungs and intestines [246]. Excessive suppression of Th1 and IFN-γ production is related, on the other hand, to an inadequate rise in the i2-response in severe cases of COVID-19, and additional causes of IL-6 and IL-10 overproduction may be detected [247,248]. In such circumstances, low levels of IFN-γ in the blood are linked to the severity of the COVID-19 course [249].

Lymphopenia, which is related to decreased amounts of CD8+ T cells, as well as CD4+ Th and Treg cells in the blood, though to a lesser extent of decrease in B cells and NK cells, is another sign of immunological dysfunction in COVID-19 [225,250,251]. Furthermore, the severity of the patient’s condition is related to the degree of lymphopenia [250,252]. The number of neutrophils in COVID-19, on the other hand, frequently increases [253]. As the disease worsens, the neutrophil/lymphocyte ratio, which is characteristic of COVID-19, rises [254,255]. Many acute viral infections cause transient lymphopenia, but it usually resolves quickly [256,257]. Lymphopenia in COVID-19, on the other hand, can be more severe or long-lasting than in many other viral infections [248]. The following are the most likely causes of lymphopenia [251,258–260]:

• Migration of cells to the focus of inflammation;

• Direct infection of lymphocytes expressing ACE2 and other SARS-CoV-2 receptors, followed by their apoptosis or cytolysis;

• Apoptosis and pyroptosis of hyperactivated cells not infected with SARS-CoV-2;

• Metabolic and neuroendocrine changes caused by a viral infection lead to depletion and impairment of lymphoid cell regeneration.

Notwithstanding, the duration of lymphopenia in COVID-19 (up to several months after recovery) casts doubt on the essential role of lymphocyte migration to the inflammatory focus and infection of lymphocytes as the leading causes of lymphopenia.

A combined increase in the levels of IFN-γ and TNF-α plays a unique role in lymphocyte apoptosis in cytokine storm syndrome [261]. Both of these pro-inflammatory cytokines are linked to the immune response’s main antiviral vectors, i1, and TNF-α, as well as i3 [5]. High concentrations of these cytokines, on the other hand, can result in insufficient immune cell activation, dysfunction, and apoptosis. Patients with severe COVID-19 have a lower Treg/Th17 ratio, which is associated with high levels of proinflammatory cytokines and neutrophilia in the blood [262]. IL-17 and GM-CSF levels are elevated in patients with severe COVID-19 (i3 products). Furthermore, the recruitment of neutrophils, which is mediated by Th17 cells, has been shown to explain the destruction of lung tissue [263].

In severe cases, high values of cytokinemia in the form of a cytokine storm phenomenon are a sign of systemic inflammation, which is critical for the life of patients, and in some cases, MAS-like syndrome (macrophage activation syndrome) [4]. Furthermore, as previously mentioned, increased Th1 and M1 activation might harm tissues in the inflammatory foci. As a result, the evidence on IFN-’s pathogenetic role in COVID-19 is conflicting. Some publications point to IFN-’s protective role in antiviral protection as well as the efficacy of IFN- preparations in the treatment of this condition [264]. 

Other studies link elevated IFN levels in the blood with the severity of COVID-19 patients’ symptoms [265], as well as the ineffectiveness of IFN in antiviral protection of airway epithelial cells and its potential to induce ACE2 expression on intestinal epithelial cells [266]. The i1 factors promote the utilization of already infected epithelial cells but only weakly prevent their infection with SARS-CoV-2, which appears to be limiting the antiviral benefits of the i1 response in COVID-19.

The following are some of the mechanisms through which SARS-CoV-2 induces immunological dysfunction:

• Inhibition of MHC-I in infected cells, which makes it difficult for CTL to recognize them (orf8, Table 2);

• Screening of antigenic determinants of the S-protein by sugars to prevent the recognition of its antigenic sites by antibodies [75,76];

• Binding of orf8 to the IL-17 receptor and its activation on immunocompetent cells, which can contribute to immune imbalances [201];

• Possible APC dysfunctions associated with the action of the SARS-CoV-2 S-protein on PRR, SR, and other receptors on these cells (Table 1);

• Disturbance in immunocompetent cells of the balance between various signaling pathways and mechanisms of cellular stress by many factors of SARS-CoV-2 pathogenicity.

Antigen-specific T cells in COVID-19 were found to exhibit early differentiated effector memory phenotypes early in the recovery phase [267]. Patients with severe COVID-19 had a considerably higher frequency, breadth (diversity of subpopulations), and magnitude of memory T cell responses than patients with a moderate course of the disease, with the most prominent responses being elicited by proteins S, M, N, and orf3a [268,269]. Seventeen years after the 2003 SARS outbreak, people who have recovered from SARS (a disease caused by SARS-CoV-1) have long-lived memory T cells that respond to the SARS-CoV-1 N protein. These T cells showed persistent cross-reactivity with the N-protein SARS-CoV2 [269]. However, the role of memory T cells in preventing SARS-CoV-2 invasion and COVID-19 complications is currently not fully understood.

Another problem in the development of an adaptive immune response in COVID-19 is the potential for autoimmune response development.

5.2. Possible Causes of the Autoimmune and Anti-Inflammatory Process in COVID-19

An autoinflammatory response resulting from antigen-specific activation of innate immunity components, or the action of autoantigen-specific T cells and antibodies, or a combined form [270] can cause damage to tissues. These common pathogenetic patterns of many infectious processes can manifest themselves in COVID-19 [243,271].

An autoimmune response directed against tissues is the sword of Damocles for highly organized species of vertebrates and humans [272]. Organisms with adaptive immunity have multi-stage barriers to the initiation and development of autoimmune response and an autoimmune process (autoimmune inflammation). However, all these barriers can be overcome in the presence of a genetic predisposition to the action of various triggering ontogenetic and environmental factors of autoimmunity [273–275].

The following factors play a crucial role in autoimmune aggression during infection [276–278]:

(1) Molecular mimicry of viral proteins

(2) “Bystander activation”–the release of autoantigens from tissue damaged by viruses and inflammation.

(3) Violation of biological barriers in immune privileged organs (central nervous system, eye, testes, placenta), providing accessibility for adaptive immunity of potential autoantigens.

(4) Polyclonal activation of lymphocytes as a result of the action of superantigens (SAg) or for other reasons (potentially autoreactive clones of T and B lymphocytes can also be activated).

(5) “Epitope spreading”–when the targets of autoimmune responses do not remain fixed but can be expanded by including other epitopes on the same protein or in other proteins in the same tissue.

It is important to remember that not every process of polyclonal lymphocyte activation leads to an autoimmune response, and not every autoimmune response results in tissue damage and the development of an autoimmune pro-inflammatory process, which does not always lead to the development of a formal (canonical) autoimmune disease [279].

Because of SARS-molecular CoV-2’s mimicry, the virus’s and human proteins have analogous peptide sequences and immune responses against SARS-CoV-2 are directed toward human proteins. As a result, the structural proteins S and E have several areas homologous to human proteins [280]. Therefore, the E-protein may play a role in the activation of an autoimmune response (after the viral particle has been degraded). Orf3a, orf7a, orf7b, orf8, and orf9b, non-structural proteins of SARS-CoV-2, may also be involved in this process [280]. In particular, molecular mimicry was revealed between the human SARS-CoV-2 and HSP proteins (60 and 90), which was linked to Guillain-Barré syndrome and other autoimmune illnesses [281]. It is worth noting that COVID-19’s immunological response (to HSP) can damage the vascular endothelial lining [282].

In COVID-19, it is currently hypothesized that superantigen-dependent (Sag) immune dysfunction pathways are also implicated in autoimmune and auto-inflammatory processes. Superantigens (Sags) are powerful polyclonal lymphocyte activators that are resistant to proteases and thermal denaturation [283,284]. The principal pathogenic activity of SAg is nonspecific binding to the β -chain of the TCR (less frequently to the α -chain) and simultaneously to? MHC-II (less frequently MHC-I) on the APC, resulting in polyclonal activation of T cells with TCR, including potentially autoreactive clones [285] (Figure 5).

Figure 5. The induction of a clonal response of CD4+ T lymphocytes to particular antigenic peptides in association with MHC-II proteins to APC (A) and a polyclonal response (B) as a result of the action of superantigens. MHC-II proteins are displayed in blue, antigens (Ag, SAg) are shown in red, chains of the T-cell receptor (TCR) are shown in light green, TCR antigen-specific (hypervariable) sites are indicated in dark green, and the CD4 coreceptor is shown in yellow. Arrows indicate antigen and receptor designations.

Superantigens can activate up to 20–25 percent of T cells, compared to only 0.01% in the classical response, and at significantly greater Ag concentrations than SAg [284,286]. Most SAgs appear to have a common MHC-II binding site (called the generic site) that is unaffected by other Ags. Furthermore, each SAg has a preference for specific MHC alleles, which serve as possible genetic risk factors for autoimmune diseases [286]. SAg’s activating effect on T cells and B lymphocytes (expressing MHC-II), as well as innate immune cells, can eventually result in a cytokine storm and toxic shock [284,287].

Data have recently emerged relating the onset of multisystem inflammatory syndrome in children (MIS-C) to the probable impacts of SAg and the emergence of an autoinflammatory process in COVID-19. Moreover, MIS-C is a delayed and severe consequence of SARS-CoV-2 infection that affects previously healthy children [288,289]. It mimics toxic shock syndrome and certain symptoms of Kawasaki’s illness. Adults have been diagnosed with a comparable condition (multisystem inflammatory syndrome in adults, MIS-A) [290]. The MIS-C and MIS-A hypotheses [288–291] look at the pathophysiology of these disorders through the lens of autoinflammation and autoimmunity. In this scenario, the SAg-like motif is located close to the SARS-CoV-2 spike protein’s S1/S2 cleavage site [291]. The area containing this motif has a strong affinity for the V-domains of both the α- and β-chains of the TCR, and it shares structural similarities with Staphylococcal enterotoxin B (SEB), one of the most potent SAg [292,293]. SEB binds not only MHC-II and TCR proteins but also contact interaction receptors CD28 (on T cells) and B7 (on APC), which play a key role in the activation of these cells, including the generation of proinflammatory cytokines [294].

The SARS-CoV-2 S-protein can form a ternary complex: S + TCR + MHC II, according to in silico computational models [295]. A rare mutation of the S protein (D839Y/N/E) from the European strain of SARS-CoV-2 [295] can enhance the virus’s interaction with T cells. The hyperinflammatory polyclonal proliferation of T-lymphocytes in MIS-C has also been linked to MHC-I, or more specifically, the MHC-I alleles A02, B35, and C04 [296]. Patients with MIS-C had a distorted TCR memory T cell repertoire, autoimmune IgG reactive to endothelium and other tissues, and hyperactivated cytotoxic CD8+ T cells and NK cells [297–299]. Overall, MIS-C is a serious but rare COVID-19 complication. Secondary hemophagocytic lymphohistiocytosis is another serious COVID-19 consequence linked to polyclonal activation of lymphocytes and aberrant activation of innate immune cells (HLH). It frequently presents as a MAS-like syndrome, which may be one of the mechanisms for the development of a cytokine storm and systemic inflammation, both of which are life-threatening [4]. 

It is worth remembering that systemic inflammation is a multifaceted, phase-specific process with hyperallergic and depressed manifestations [272,300]. As a result, a cytokine storm, if we define it as critical cytokine levels, should have quantitative characteristics that greatly exceed reference values, such as TNF-α concentration in blood plasma > 200 pg/mL (at N 8 pg/mL) and IL-6 concentration in blood plasma > 1000 pg/mL (at N 5 pg/mL) [301]. Lower cytokine concentrations, in our opinion, necessitate the adoption of integral criteria for assessing the systemic inflammatory response and systemic inflammation. Currently, there are no quantitative verification criteria that distinguish cytokine storm syndrome from non-critical forms of hypercytokinemia [302]. This scenario appears to allow it to be mislabeled as a “cytokine storm,” which more closely resembles a “storm in a glass of water,” “storm in a teacup,” or “storm in a cup of water” COVID-19 [4].

Meanwhile, the processes of polyclonal lymphocyte activation and latent autoimmune response can affect a range of systems, including the immunological, neuroendocrine, cardiovascular, pulmonary, cutaneous, and digestive systems [286,303]. However, in the presence of additional risk factors, these same processes can result in the development of classical autoimmune diseases after COVID-19 [304–306]. 

Nevertheless, the chances of developing these diseases as a result of the COVID-19 transfer are modest. In COVID-19, nonclassical symptoms of an autoimmune response are more prevalent. Thus, SARSCoV-2 protein mimicry of three human proteins, DAB1, AIFM, and SURF1, found in the pre-Bötzinger complex (preBötC) of the brain stem, may contribute to COVID-19 respiratory failure [307]. Other autoantibodies common in many autoimmune illnesses, such as antinuclear antibodies (ANAs), anti-cytoplasmic neutrophil antibodies (ANCA), and antiphospholipid antibodies (APL), were discovered in 45 percent of COVID-19 patients [308]. However, in most situations, the pathogenetic relevance of these autoimmune factors remains unclear.

The problem of “long COVID”, also known as “condition after COVID-19, unspecified” (International Classification of Diseases-10, ICD-10), “post-COVID-19 syndrome”, and “post-acute COVID,” may make the identification of hidden indications of an autoimmune response more important. Persistent fatigue, anhedonia, muscle weakness, sleep issues, anxiety or even depression, difficulty concentrating, myalgia and arthralgia, and autonomic dysfunction are all symptoms of long COVID [309–313]. In roughly 20% of patients, these symptoms persist for 3–6 months or longer after they have been cured of COVID-19. Long COVID can also be found in patients with mild COVID-19 [314]. As a result, following severe COVID-19 [311], long COVID requires special attention. The mechanisms of long COVID pathogenesis are yet unknown. Organ damage, post-viral syndrome, post-critical care syndrome, and other factors have been postulated as possible causes. Given the immunopathogenesis of COVID-19, its role in long-term immunological dysfunction, particularly the autoimmune response, appears to be a distinct possibility. 

In addition, new evidence suggests that SARS-CoV-2 can infect the central nervous system and the brain cells, particularly microvascular endothelial cells [315,316]. Hypoxia and cytokine storms, when combined with viral invasion, can compromise the blood-brain barrier (BBB) and cause brain tissue damage [306,307]. SARS-CoV-2 is thought to cause irreversible consequences in the brain due to BBB degradation, including dementia in predisposed people [315]. It is worth noting that BBB destruction plays a key role in the immunopathogenesis of autoimmune neurological disorders, as this vascular interface serves as an entryway for peripheral immune cells and effector molecules to reach an immune-privileged target organ [317–319].

6. Conclusions

Despite the large-scale sanitary and preventive efforts taken over the last two years, the COVID-19 pandemic remains active, and optimistic forecasts about its end have yet to be justified. There is currently no scientifically validated forecast of the infection’s future behavior. SARS-CoV-2 can diminish its virulence with a relatively favorable variant, and its offspring strains or species will vanish or, like “colds”–CoV (HCoV-OC43 and HCoV-HKU1), induce episodes of common seasonal respiratory infections [320]. However, because of the virus’s unique biochemistry, less positive alternatives for adapting SARSCoV-2 to human society are also possible.

SARS-CoV-2 has a high level of genetic variability, a large genome, and a large proteome, all of which are accompanied by pronounced polyfunctionality of its proteins. As a result, SARS-CoV-2 can infect target cells in the upper respiratory tract, epithelium of the alveoli (mainly type 2 astrocytes), and the intestines, after initial contact. SARS-CoV-2 also inhibits the early protective effects of type I and III IFNs and other innate antiviral defense systems. SARS-CoV-2 additionally causes the formation of symplasts of infected and healthy cells and extracellular vesicles containing viruses, which help it bypass the epithelium’s biological barriers and spread throughout the body. Since the SARS-CoV-2 S-protein can recognize not only the major receptor (ACE2) and its coreceptors but also other (alternative) receptors, SARS-CoV-2 can potentially infect a wide variety of target cells in the host organism’s tissues.

Like many other acute viral infections, COVID-19 can, with a progressive course, implement four main stages of pathogenesis:

(1) Invasion and forced replication of the virus in integumentary tissues, primarily in the epithelium of the respiratory tract and intestines. The key mechanisms of this stage are the recognition of target cells by the virus through receptor structures and the blockade of the primary (early) IFN-I-III response.

(2) Virus-induced loss of the barrier functions at the focus of inflammation through the dysregulation of the innate and then the adaptive immune response controlled by the pathogenicity factors. The selective suppression of specific antiviral mechanisms, the indiscriminate polyclonal activation of lymphocytes, the development of hip inflammation according to the variant of an autoinflammatory process, and in some cases, a latent or even clinically manifest autoimmune process are all factors that assist viral expansion during this period.

(3) Generalization of the virus in the body, systemic changes in the immune status, and other parameters of homeostasis with a high risk of critical complications.

(4) The stage of long-term consequences of a viral infection associated with the long-term persistence of the virus in the body, the consequences of primary (viral) and secondary (autogenous) tissue damage, including possible breach of the BBB integrity, endothelial dysfunction, hypercoagulation, and persistent changes in the immune status.

SARS-CoV-2 features a particularly high degree of genetic variability, owing to its large genome and proteome size, as well as its proteins’ pronounced polyfunctionality. The high variability of the spike protein, in particular, influences the possibility of invasion of many different cell types, including alveolates, not only via the main receptor (ACE2) but also via a variety of coreceptors and alternative receptors (Table 1). As a result, the effects of the SARS-CoV-2 S protein on immunocytes’ PRR (including TLR), SR, IL-17 receptor, and other sensory molecules can be dysfunctional to the immune system, resulting in tissue damage and viral replication in various cells.

The ability of the S-protein to induce the formation of cellular symplasts and to be screened by sugars, the potential for the development of the ADE phenomenon, and the use of extracellular vesicles by the virus may be its mechanisms of protection against the factors of the humoral immune response, including those associated with vaccines.

Almost all SARS-CoV-2 proteins (Table 2) are multifunctional pathogenic factors that act on various mechanisms of antiviral immunity. However, their most widespread effect is probably associated with the blockade of almost all stages of initiation and implementation of the IFN response (Figures 3 and 4). These mechanisms allow the virus to effectively overcome the barrier functions of integumentary tissues in the initial period of the disease and contribute to the dysfunction of the immune response associated with IFN-γ at later stages of the infectious process. In addition, this circumstance reduces the efficacy of the use of IFN synthesis inducers as the COVID-19 therapy

Another feature of the pathogenicity factors of SARS-CoV-2 is its ability to act on almost all the main processes of proinflammatory cellular stress development in various types of cells, including the formation of inflammasomes, oxidative stress, the response of noncoding RNAs, autophagy, expression of universal transcription factors of cellular stress (for example, NF-κB), and the formation of a secretory phenotype associated with cytokine networks. These mechanisms provide the virus with an additional opportunity to replicate in various cells, induce immune dysfunction, and form abnormal inflammation patterns.

There is now no doubt that COVID-19 can develop an auto-inflammatory and autoimmune process, which may well lead to complications such as MAS-like syndrome and MIS-C/MIS-A. These complications, along with other causes, contribute to systemic microcirculatory disorders and other life-critical manifestations of systemic inflammation. Therefore, all of the main factors for the emergence of an auto-immune response can potentially manifest themselves in COVID-19, including molecular mimicry of many SARS-CoV-2 proteins, “Bystander activation”, “Epitope spreading” (in conditions of tissue destruction), breach of the biological barriers in immune privileged organs, polyclonal activation of lymphocytes, and pathological activation of APC (as a result of the action of SAg).

Currently, a comprehensive assessment of these mechanisms is one of the most relevant scientific directions for studying the pathogenesis of not only COVID-19 but also other viral infections [320–324].

A special problem of the infection under consideration is the “long COVID” phenomenon, primarily associated with long-term disorders of the central nervous system, persistent changes in the immune system (including long-term lymphopenia), and complications in other organs. Probably, we will see a more complete picture of the pathogenesis of “long COVID” as a result of further research, including clarification of the role of autoimmune and autoinflammatory processes, impaired BBB, viral persistence, and comorbid vascular pathologies.

The warning signs of COVID-19 are:

• The presence, in some cases, of long-term persistence of SARS-CoV-2 in the body in immunodeficient patients [324];

• The presence, in about every fifth case, of long-term consequences caused by the transferred infection in the form of a long COVID;

• Longer (in comparison with SARS-CoV-1 and MERS-CoV) retention of SARS-CoV-2 RNA in biological fluids in COVID-19 patients (up to 1–2 months) [325], as well as the detection of SARS-CoV-2 RNA in more than one out of ten patients with relapse within 60 days after recovery from primary infection [326];

• The presence of the COVID-19 clinic in some cases of relapse and the occurrence of infection in vaccinated patients who initially did not have clinical signs of immunodeficiency states [327,328];

• The development of a latent and, in some cases, clinically significant auto-immune response to COVID-19;

• The potential ability of the virus to actively overcome the factors of not only innate but also adaptive immune response

Thus, depending on the characteristics of a particular strain of SARS-CoV-2, environmental factors, the presence of comorbid pathologies, and the state of the immune system of the body, the dynamics of COVID-19 may stop at its initial stages (including subclinical variants) or reach the terminal, critical life stages of the disease associated with multiple systemic disorders of homeostasis (Figure 6).

Figure 6. COVID-19 pathogenesis (pathogenesis) stages. (1) Infection of integumentary tissue cells, overriding of IFN-dependent systems of innate immunity cellular defense, blockade or hyperstimulation of cellular stress signaling pathways, and other consequences of cellular distress. (2) Dysfunction of adaptive immunity and canonical inflammation processes in the zone of invasion, breach of the focus of inflammation’s barrier function, dysfunction of the damaged organ, and virus generalization in the body. (3) Increasing changes in the body’s homeostasis, formation of systemic alteration phenomena, and development of systemic inflammation. IFN induction routes and IFN action in infected cells are indicated by blue arrows. Other arrows indicate the directions in which distinct pathogenetic processes interact with one another. Blocks of IFN generation and their impact on cells that generate SARS-CoV-2 proteins are shown in red lines. Processes associated with immune dysfunction are highlighted in blue boxes; autoinflammatory processes are highlighted in red; the focus of inflammation dysfunction is highlighted in green boxes; tissue dysfunction is highlighted in black boxes, and systemic inflammation is highlighted in red fill boxes.

Author Contributions:

Conceptualization, E.G., and V.C.; writing–original draft preparation, E.G., and L.S.; writing–review and editing, E.G., A.S., V.C.; funding acquisition, A.S. All authors have read and agreed to the published version of the manuscript.

Funding:

The reported study was funded by RFBR and NSFC, project number 21-51-55003, and partly by the Government contract of the Institute of Immunology and Physiology.

Institutional Review Board Statement:

Not applicable.

Informed Consent Statement:

Not applicable.

Conflicts of Interest:

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

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