SARS-CoV-2-Specific Immune Response and the Pathogenesis of COVID-19

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 of 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 hyperergic mechanisms of systemic inflammation is critical at this stage of infection.

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

Figure 1

The principal structure of SARS-CoV-2.

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 cells types with SARS-CoV-2, other host proteases can potentially participate in similar cleavage of the SARS-CoV-2 S protein [15].

Figure 3

The primary phases of the essential signaling pathway for IFN-I-III production are inhibited by SARS-CoV-2 proteins. The signaling pathway for inducing IFN-I-III production is indicated by the blue color. The green color denotes post-transcriptional steps in IFN-I-III production and secretion. The blocks of the corresponding stages of IFN-I-III induction, production, and secretion that are produced by SARS-CoV-2 proteins are shown in red. The direction of action effects is indicated by arrows.

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 [216,217,218,219]. 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.

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, and 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.

Figure 6

COVID-19 pathogenesis (pathokinesis) 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 the 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.