COVID-19 Immunology: How SARS-CoV-2 Infections Damage The Immune System

COVID-19 Immunology: This is a summarized overview for readers to comprehend how SARS-CoV-2 Infections damages both the Innate and Adaptive components of the human host immune system based on 27 selected studies that Thailand Medical News selected.


 
Comprehending the immune damage mechanisms provide essential guidelines for clinical treatment and immune prevention strategies. Numerous studies have shown that SARS-CoV-2 infection not only triggers the hyperinflammatory response, delayed secretion of type I interferon (IFN-I), and hyperactivation of the complement system commonly seen in other pathogen infections but also directly infects the host's innate immune cells and secondary lymphoid organs, ultimately leading to immune exhaustion.
 
The issue of immune exhaustion is of great concern and is an important component of COVID-19 Immunology.This immune exhaustion can result in uncontrolled infections among the aged and immunosuppressed populations, clinically manifested as critical illness or even death. They also contribute to many manifestations see in Long COVID individuals.
 
Innate Immune System Damage by SARS-CoV-2 Infection
 
Hyperinflammatory Response
The innate immune system is mainly composed of innate immune cells such as mononuclear macrophages and neutrophils, as well as their secreted cytokines, which serve as one of the first defensive lines against viral infections. Unlike other respiratory viruses, SARS-CoV-2 can infect not only human type I alveolar cells but also innate immune cells like mononuclear macrophages, neutrophils, and dendritic cells. This infection can result in the accumulation of various cytokines and chemokines in the serum and bronchoalveolar lavage fluid, leading to increased capillary permeability, alveolar fluid accumulation, and impaired ventilation function. Ultimately, this hyperinflammatory response can cause capillary leakage syndrome, leaky guy syndrome, sepsis and multiple organ dysfunctions in infected individauls.
 
Over-Activation of the Complement System
The complement system is an essential part of the innate immune system. Appropriate activation can lead to the phagocytosis and lysis of invading pathogens, but overactivation can intensify the inflammatory response, leading to lung and epithelial cell injury, microangiopathy, and thrombogenesis, ultimately resulting in multiorgan failure in patients. For instance, complement components C3a, C5a, and sC5b-9 are deposited in alveolar type II cells of patients with COVID-19. In addition, C5a-C5aR1 can activate neutrophils and mononuclear cells to secrete inflammatory factors, forming a hyperinflammatory response. Blocking C5a-C5aR1 has been identified as an effective new strategy in severe COVID-19 treatment.
 
Delayed Secretion of Type I Interferon or IFN-I,
Type I Interferon or IFN-I, primarily produced by innate immune cells, plays a crucial role in suppressing viral replication and enhancing antiviral immunity. Research has shown that SARS-CoV-2 virus proteins can inhibit the expression of several key molecules that regulate the IFN-I gene (Ifn-I) transcription pathway. Additionally, the overactivation of the IFN-I signal pathway contributes to the delayed secretion of interferon in patients with severe COVID-19.
 
SARS-CoV-2 microRNA (miRNA) SCV-miR-ORF1ab-1-3p and SCV2-miR-ORF1ab-25p have been found to play a role in immune escape by targeting many genes in the IFN-I signal pathway. It should be noted that IFN-I has a protective role in the early phase of the disease, but can be damaging in the late phase.
 
Hyperactivation of NLRP3 Inflammasomes
The NLRP3 inflammasome is an essential component of the innate immune system that plays a crucial role in controlling viral infections. SARS-CoV-2 infection can trigger the activation of the NLRP3 inflammasome, leading to the release of IL-1β, IL-18, and gasdermin D, and consequently causing lung tissue damage in COVID-19 patients. This suggests that dysregulation of the NLRP3 inflammasome might contribute to the severity of COVID-19.
 
It has been reported that SARS-CoV-2 infected human lung-resident macrophages activate NLRP3 inflammasomes, thereby contributing to the hyperinflammatory state of the lungs. Past studies also showed that lung sections from patients with fatal COVID-19 who had died of cardiopulmonary arrest expressed significantly high levels of NLRP3 inflammasome molecules. Further studies demonstrated that SARS-CoV-2 encoding ORF3a, ORF-3b, N, and E antigens can each activate the NLRP3 inflammasomes. Therefore, targeting NLRP3 inflammasomes represents a promising therapeutic approach to combat COVID-19.
 
Adaptive Immune System Damage by SARS-CoV-2 Infection:
 
The adaptive immune system, mainly composed of T cells and neutralizing antibodies, plays a critical role in defending the body against infections. However, SARS-CoV-2 infection can cause significant damage to the adaptive immune system, leading to impaired immune responses and increased severity of COVID-19
 
Lymphopenia
Lymphopenia is characterized by a decreased number of lymphocytes, which can develop in 50% to 83% of severe COVID-19 patients. The protective effect of adaptive immunity is mainly accomplished by T cells and neutralizing antibodies, with T-cell immunity playing a crucial role. Inflammatory factors can directly induce T cell apoptosis or pyroptosis, also known as inflammatory cell death, resulting in a severe reduction in the quantity of high antiviral activity IFN-γ+/TNF-α+/IL-2+/granzyme B+/CD4+ T cells and memory CD3+/CD45RO+/CD4+ T cells in the body. Lymphopenia is therefore considered a critical factor for poor prognosis in patients with severe COVID-19.
 
Acute T-cell Exhaustion
Besides lymphopenia, patients with COVID-19 may also experience acute functional exhaustion of T cells, another aspect of acquired immune system damage. Inhibitory receptor molecules, such as PD-1, TIM-3, and LAG-3, are highly expressed in CD3+ T cells in peripheral blood mononuclear cells of patients with severe COVID-19 induced by acute SARS-CoV-2 infection. The frequency of NKG2A+/PD-1+/CTLA-4+/TIGIT+ exhaustion CTL in dead patients or patients with severe COVID-19 is significantly higher than in moderate/mild patients, suggesting that it is associated with poor prognosis.
 
Subsequent single-cell RNA sequencing (scRNA-seq) has revealed that T cells in patients with COVID-19 exhibit exhaustion characteristics, including the expression of tissue-resident and memory phenotype (ZNF683+ and ITGAE+); high expression of inhibitory molecules PD-1, TIM-3, HAVCR2, LAG3, and CTLA-4; high expression of proinflammatory factors CD70, COTL, and HMGB1; and stress-related molecules HSPD1, HSP90AA1, and BIRC5. These findings indicate that SARS-CoV-2 triggers immune escape by inducing acute T-cell exhaustion in patients with COVID-19.
 
Previously, T-cell exhaustion was thought to occur only in chronic infections or tumors, but recent study findings showed that it could also happen in acute infections among individuals with poor immune homeostasis.
 
Recently, a retrospective analysis and found that 13 melanoma patients who received PD-1 monoclonal antibody therapy experienced mild or asymptomatic SARS-CoV-2 infections. This finding demonstrates that reversing acute T-cell exhaustion is both effective and safe, and could potentially be applied in the treatment of critical COVID-19 cases.
 
Conclusion
Understanding the immune damage mechanisms of COVID-19 is crucial for developing effective treatment and prevention strategies. The complex interactions between the virus and the host's immune system, including hyperinflammatory responses, delayed IFN-I secretion, complement system overactivation, and NLRP3 inflammasome dysregulation, lymphopenia, acute T-cell Exhaustion contribute to the disease's severity.
 
A better understanding of these mechanisms is crucial for the development of effective treatments and prevention strategies against COVID-19. Future research should focus on identifying new therapeutic targets and optimizing existing treatments to improve patient outcomes and mitigate the impact of the virus on the innate and adaptive immune system.
 
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