Immunology of SARS-CoV-2 infection

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Abstract

According to WHO data, about 800 million of the world population had contracted a coronavirus infection caused by SARS-CoV-2 by mid-2023. The properties of this virus allowed it to circulate in the human population for a long time, evolving defense mechanisms against the host immune system. The severity of the disease depends largely on the degree of activation of the systemic immune response, including overstimulation of macrophages and monocytes, cytokine production, and triggering of adaptive T- and B-cell responses while SARS-CoV-2 evading from the immune system action. In the review we discussed the immune responses triggered in response to SARS-CoV-2 virus entry into the cell and the malfunctions of the immune system leading to the development of severe disease.

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About the authors

A. G. Gabdoulkhakova

Kazan (Volga region) Federal University; Kazan State Medical Academy, Branch Campus of the Federal State Budgetary Educational Institution of Further Professional Education «Russian Medical Academy of Continuous Professional Education» of the Ministry of Healthcare of the Russian Federation

Email: AiGGabdulhakova@kpfu.ru
Russian Federation, 420008 Kazan; 420012 Kazan

R. N. Mingaleeva

Kazan (Volga region) Federal University

Email: AiGGabdulhakova@kpfu.ru
Russian Federation, 420008 Kazan

A. M. Romozanova

Kazan (Volga region) Federal University

Email: AiGGabdulhakova@kpfu.ru
Russian Federation, 420008 Kazan

A. R. Sagdeeva

Kazan (Volga region) Federal University

Email: AiGGabdulhakova@kpfu.ru
Russian Federation, 420008 Kazan

Yu. V. Filina

Kazan (Volga region) Federal University

Email: AiGGabdulhakova@kpfu.ru
Russian Federation, 420008 Kazan

A. A. Rizvanov

Kazan (Volga region) Federal University; Academy of Sciences of the Republic of Tatarstan

Email: AiGGabdulhakova@kpfu.ru

Department of Medical and Biological Sciences

Russian Federation, 420008 Kazan; 420111 Kazan

R. R. Miftakhova

Kazan (Volga region) Federal University

Author for correspondence.
Email: AiGGabdulhakova@kpfu.ru
Russian Federation, 420008 Kazan

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2. Fig. 1. The mechanism of entry and exit of the SARS-CoV/SARS-CoV-2 virus into the cell. The first stage of interaction involves recognition of the S protein of the virus by the ACE2 receptor (1), the second stage can differ and go either along the membrane fusion pathway (2 A) or along the endosome formation pathway (2 B). Endosomes can fuse with lysosomes containing cathepsin L and B and other proteases, which ensures the cleavage of the S protein and further fusion of the endosome membrane and the virus (3). The release of viral RNA into the cytosol leads to the translation of viral polymerase and other viral proteins (4), assembly and release of virions (5). Both the spike protein and ACE2 can be targets for proteases, when the so-called shedding of the extracellular domain of ACE2 from the cell surface occurs (compiled according to [7–10])

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3. Fig. 2. Schematic representation of the formation of a multinuclear syncytium during infection of cells with SARS-CoV-2. The entry of the virus into cells is triggered by the interaction between the S protein of the virus and the ACE2 receptor of the cell (1). The appearance of the S protein on the plasma membrane occurs during the fusion of the virion with the cell (2A) or during infection via the endosomal pathway (2B). In this case, due to the low pH in the endosome, proteolytic cleavage of the S protein (3), release of the genome, its replication and synthesis of viral proteins in the endoplasmic reticulum (4) occur. Part of the S protein, due to its structural features, is transported and integrated into the plasma membrane. Thus, the presence of ACE2 and S protein fusion molecules on the membranes of neighboring cells promotes their fusion (5). Abbreviations: ACE2 – angiotensin-converting enzyme 2, TMPRSS2 – transmembrane serine protease 2

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4. Fig. 3. Schematic representation of the mutual activation of immune cells during SARS-CoV-2 infection. The innate immune response is activated within a few hours after infection with the virus and is accompanied by the release of a number of antiviral molecules. APCs (macrophages, dendritic cells and, to some extent, granulocytes) phagocytose the pathogen, fragment it into small peptides, which are presented on their surface using the major histocompatibility complex class II (MHC-II). The interaction of MHC-II and the T cell receptor activates CD4+ T helper cells, as well as B and CD8+ cells. Activation of T helper cells leads to their differentiation into various subtypes with specific functions mediated by cytokine secretion and cell-to-cell contacts. B cells that differentiate into plasma cells secrete antibodies that prevent the viral particle from penetrating healthy cells. Th2 lymphocytes contribute to the implementation of the humoral response by providing a second signal to B cells, mainly due to the secretion of IL-4 and the CD40/CD40L interaction. Some CD4+ cells become follicular helper cells (Tfh), which regulate important interactions in the germinal centers required for the maturation of memory B cells and long-lived high-affinity antibody-producing plasma cells. Another pool of CD4+ T cells differentiates into a pool of memory T helper cells (Tmem). Th1 play a critical role in the formation of a cellular response. They initiate the activation of MHC-I CD8+ cytotoxic T lymphocytes (Teff), simultaneously interacting with APCs. Activated Teff induce apoptosis of cells infected with the SARS-CoV-2 virus. Some Teff differentiate into cytotoxic memory T cells (Tem), which are responsible for rapid restoration of the cellular immune response upon secondary contacts with the antigen. A similar mechanism of destruction occurs when NK cells interact with a virus-infected cell. However, excessive activation of immune cells leads to a decrease in the number of lymphocytes due to cell death, moreover, lymphocytes often exhibit an exhaustion phenotype with the expression of higher levels of exhaustion markers PD-1, Tim-3 or NKG2A. Abbreviations: Act – activation, PS – signal transduction, CoS – costimulation, Ex – expression

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5. Fig. 4. Schematic representation of the development of hyperinflammation and cytokine release syndrome in severe COVID-19. SARS-CoV-2 infects epithelial and immune cells, causing tissue damage and the release of inflammatory cytokines IL-1, IL-6, IL-12, and TNF-α. Viral antigens and inflammatory cytokines recruit innate immune cells (monocytes, macrophages, neutrophils, dendritic and NK cells) to the site of inflammation and activate adaptive immune cells (CD4+ and CD8+ T cells), inducing myelopoiesis and granulopoiesis, as well as sustained production of excessive circulating cytokines, which further exacerbate epithelial damage. Immunopathological manifestations of COVID-19 include lymphopenia, monocyte and macrophage dysregulation, neutrophilia, ADE, decreased or delayed IFN-I, and development of CRS. Peripheral monocytes show a phenotype shift from CD16+ to CD14+, and the number of macrophages released into BAL increases due to their migration from the blood to the lungs. Decreased or delayed IFN-I hampers viral clearance and causes paradoxical hyperintensity inflammation, resulting in a worse prognosis in patients with COVID-19. Excessive production of systemic cytokines induces macrophage activation and hemophagocytic lymphohistiocytosis, resulting in anemia, and also causes impaired vascular hemostasis, leading to capillary leak syndrome, thrombosis, and intravascular coagulation syndrome. Together, these events lead to acute respiratory distress syndrome, multiple organ failure, and death (adapted from [61–63]). Abbreviation: ARDS – acute respiratory distress syndrome

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6. Fig. 5. Amino acid substitutions in the SARS-CoV-2 spike protein that affect the virus's transmissibility and ability to evade the immune response. (Data references are given in the text)

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7. Appendix. Table P1. Receptors, membrane, endosomal and secreted proteins of the human body interacting with SARS-CoV-2
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