Pathogenesis of SARS-CoV-2 and COVID-19
المؤلف:
Baijayantimala Mishra
المصدر:
Textbook of Medical Virology
الجزء والصفحة:
2nd Edition , p300-301
2025-12-21
64
When the virus enters into the host cell, the viral antigens are recognized by the various antigen presenting cells through various pattern recognition receptors. Antigen peptides are presented to CD8+ T cells along with major histocompatibility complex I (MHC). CD+ T cells get activated and develop into effector and memory cells. Effector CD8+ T cells kills the virally infected cells, whereas CD4+ T cells help the B cells to produce neutralizing antibody. Other mechanisms such as activation of natural killer cells and production of proinflammatory cytokines also adapted to restrict the viral infection. As long as the immune response is well-coordinated, it acts to clear the virus. Dysregulated and uncontrolled systemic immune response leads to exaggerated cytokine production and cytokine storm causes collateral immune damage to the host body. Cytokine storm is characterized by the increased production of proinflammatory cytokines, such as IL-1b, IL-2, IL-6, IL-7, IL-8, IL-9, IL-10, and IL-17; granulocyte-macrophage colony stimulating factor (GM-CSF); TNF-a, IFN-g and chemokines; CCL2, CCL3, CCL5, CXCL8, CXCL9, CXCL10, etc. by immune effector cells. It induces the immune-mediated damage to lungs leading to ARDS, respiratory failure, shock, tissue damage and multiorgan failure and potentially death.
Amongst the cytokines, IL-6, TNF-a, IL-17 play crucial role in immunopathogenesis. IL 6 is produced by various immune and non immune cells across multiple organ systems. Increased IL-6 results in increase vascular permeability leading to interstitial edema, vascular leakage, and hypotension. It weakens the cytotoxicity of NK cells by downregulating the perforin and granzyme b expression.
TNF-a is another potent multifunctional inflammatory cytokine produced by macro phage/monocyte. Besides its role in inducing fever, augmenting systemic inflammation and activates antimicrobial response by IL-6. However, in high level rather than resisting infection it is known to cause necrosis and accentuates T cell apoptosis. Being a potent inducer of NF-kb, it also induces the expression of multiple proinflammatory cytokine genes. TNF-a has been implicated in severe immune mediated pulmonary injury.
IL-17 cytokine is another important cytokine that is produced by Th17 cell. IL-17 plays its role by recruiting monocyte/macrophage and neutrophil to the site of infection and also stimulate the cytokine cascade like IL-6 and IL1-b.
The increase in the level of chemokines stimulates the leukocyte infiltration and aggravates the disease severity and leads to the development of pulmonary centric disease.
SARS-CoV-2 infection induces a robust humoral immune response. Like other viral infection, the antibody profile has a typical pattern of IgM and IgG antibody production. Antibodies produced are mainly against N and S proteins. Seroconversion occurs around 7–14 days of symptom onset and persists for a few weeks after clearance of the virus. IgM antibody persists for about 3 months or 12 weeks post onset of symptoms whereas IgG persists longer and may be protective in nature. The production of antibody helps the host by binding to the virus and thereby inhibits the binding and invading of virus into the host cell. However, once the virus has entered into the cell, they become inaccessible to the antibodies and cannot be neutralized by them. In SARS-CoV-2, antibody to S protein has the ability of neutralizing the virus. The level and duration of protectivity of antibody produced after natural infection is not certain which gets more complicated with appearance of virus variants.
Immunopathology: Diffuse alveolar damage is the hallmark of the ARDS. It has two phases— acute phase and organic phase. Acute phase is characterized by formation of hyaline mem brane, interstitial edema, alveolar collapse and pneumocyte desquamation and organic phase is characterized with loosely organized fibrosis and hyperplasia of type II pneumocyte. Organization of fibrosis begins at around 10 days of illness. The main histopathologic features of diffuse alveolar damage are infiltration of mononuclear cell, alveolar fibrin deposit, hyperplasia of type II pneumocytes and thickened alveolar septa.
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