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COVID-19 Immunology - Damage Of Innate And Adaptive Immune System  Mar 25, 2023  1 year, 6 months, 2 weeks, 3 days, 3 hours, 49 minutes ago

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

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COVID-19 Immunology: How SARS-CoV-2 Infections Damage The Immune System
COVID-19 Immunology - Damage Of Innate And Adaptive Immune System  Mar 25, 2023  1 year, 6 months, 2 weeks, 3 days, 3 hours, 49 minutes ago
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.
 
References:
 
Zheng Y, Zhuang MW, Han L, Zhang J, Nan ML, Zhan P, et al. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) membrane (M) protein inhibits type I and III interferon production by targeting RIG-I/MDA-5 signaling. Signal Transduct Target Ther (2020) 5(1):299. doi: 10.1038/s41392-020-00438-7
PubMed Abstract | CrossRef Full Text | Google Scholar

da Silva RP, Goncalves JIB, Zanin RF, Schuch FB, de Souza APD. Circulating type I interferon levels and COVID-19 severity: A systematic review and meta-analysis. Front Immunol (2021) 12:657363. doi: 10.3389/fimmu.2021.657363
PubMed Abstract | CrossRef Full Text | Google Scholar

Zhu Y, Zhang Z, Song J, Qian W, Gu X, Yang C, et al. SARS-CoV-2-Encoded MiRNAs inhibit host type I interferon pathway and mediate allelic differential expression of susceptible gene. Front Immunol (2021) 12:767726. doi: 10.3389/fimmu.2021.767726
PubMed Abstract | CrossRef Full Text | Google Scholar

Zheng Y, Zhuang MW, Han L, Zhang J, Nan ML, Zhan P, et al. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) membrane (M) protein inhibits type I and III interferon production by targeting RIG-I/MDA-5 signaling. Signal Transduct Target Ther (2020) 5(1):299. doi: 10.1038/s41392-020-00438-7
PubMed Abstract | CrossRef Full Text | Google Scholar

Abela IA, Pasin C, Schwarzmuller M, Epp S, Sickmann ME, Schanz MM, et al. Multifactorial seroprofiling dissects the contribution of pre-existing human coronaviruses responses to SARS-CoV-2 immunity. Nat Commun (2021) 12(1):6703. doi: 10.1038/s41467-021-27040-x
PubMed Abstract | CrossRef Full Text | Google Scholar

Tarke A, Coelho CH, Zhang Z, Dan JM, Yu ED, Methot N, et al. SARS-CoV-2 vaccination induces immunological T cell memory able to cross-recognize variants from alpha to omicron. Cell (2022) 185(5):847–59 e11. doi: 10.1016/j.cell.2022.01.015
PubMed Abstract | CrossRef Full Text | Google Scholar

Li Q, Wu J, Nie J, Zhang L, Hao H, Liu S, et al. The impact of mutations in SARS-CoV-2 spike on viral infectivity and antigenicity. Cell (2020) 182(5):1284–94 e9. doi: 10.1016/j.cell.2020.07.012
PubMed Abstract | CrossRef Full Text | Google Scholar

Cao Y, Jian F, Wang J, Yu Y, Song W, Yisimayi A, et al. Imprinted SARS-CoV-2 humoral immunity induces convergent omicron RBD evolution. Nature (2022) 614(7948):521–9. doi: 10.1038/s41586-022-05644-7
PubMed Abstract | CrossRef Full Text | Google Scholar

da Silva RP, Goncalves JIB, Zanin RF, Schuch FB, de Souza APD. Circulating type I interferon levels and COVID-19 severity: A systematic review and meta-analysis. Front Immunol (2021) 12:657363. doi: 10.3389/fimmu.2021.657363
PubMed Abstract | CrossRef Full Text | Google Scholar

Zhu Y, Zhang Z, Song J, Qian W, Gu X, Yang C, et al. SARS-CoV-2-Encoded MiRNAs inhibit host type I interferon pathway and mediate allelic differential expression of susceptible gene. Front Immunol (2021) 12:767726. doi: 10.3389/fimmu.2021.767726
PubMed Abstract | CrossRef Full Text | Google Scholar

Habel JR, Nguyen THO, van de Sandt CE, Juno JA, Chaurasia P, Wragg K, et al. Suboptimal SARS-CoV-2-specific CD8(+) T cell response associated with the prominent HLA-A*02:01 phenotype. Proc Natl Acad Sci USA (2020) 117(39):24384–91. doi: 10.1073/pnas.2015486117
PubMed Abstract | CrossRef Full Text | Google Scholar

Zheng M, Gao Y, Wang G, Song G, Liu S, Sun D, et al. Functional exhaustion of antiviral lymphocytes in COVID-19 patients. Cell Mol Immunol (2020) 17(5):533–5. doi: 10.1038/s41423-020-0402-2
PubMed Abstract | CrossRef Full Text | Google Scholar

Wauters E, Van Mol P, Garg AD, Jansen S, Van Herck Y, Vanderbeke L, et al. Discriminating mild from critical COVID-19 by innate and adaptive immune single-cell profiling of bronchoalveolar lavages. Cell Res (2021) 31(3):272–90. doi: 10.1038/s41422-020-00455-9
PubMed Abstract | CrossRef Full Text | Google Scholar

Zhang JY, Wang XM, Xing X, Xu Z, Zhang C, Song JW, et al. Single-cell landscape of immunological responses in patients with COVID-19. Nat Immunol (2020) 21(9):1107–18. doi: 10.1038/s41590-020-0762-x
PubMed Abstract | CrossRef Full Text | Google Scholar

bobcakova A, Petriskova J, Vysehradsky R, Kocan I, Kapustova L, Barnova M, et al. Immune profile in patients with COVID-19: Lymphocytes exhaustion markers in relationship to clinical outcome. Front Cell Infect Microbiol (2021) 11:646688. doi: 10.3389/fcimb.2021.646688
PubMed Abstract | CrossRef Full Text | Google Scholar

Shahbazi M, Moulana Z, Sepidarkish M, Bagherzadeh M, Rezanejad M, Mirzakhani M, et al. Pronounce expression of Tim-3 and CD39 but not PD1 defines CD8 T cells in critical covid-19 patients. Microb Pathog (2021) 153:104779. doi: 10.1016/j.micpath.2021.104779
PubMed Abstract | CrossRef Full Text | Google Scholar

Diao B, Wang C, Tan Y, Chen X, Liu Y, Ning L, et al. Reduction and functional exhaustion of T cells in patients with coronavirus disease 2019 (COVID-19). Front Immunol (2020) 11:827. doi: 10.3389/fimmu.2020.00827
PubMed Abstract | CrossRef Full Text | Google Scholar

Huber S, Massri M, Grasse M, Fleischer V, Kellnerová S, Harpf V, et al. Systemic inflammation and complement activation parameters predict clinical outcome of severe SARS-CoV-2 infections. Viruses (2021) 13(12):2376. doi: 10.3390/v13122376
PubMed Abstract | CrossRef Full Text | Google Scholar

Carvelli J, Demaria O, Vely F, Batista L, Chouaki Benmansour N, Fares J, et al. Association of COVID-19 inflammation with activation of the C5a-C5aR1 axis. Nature (2020) 588(7836):146–50. doi: 10.1038/s41586-020-2600-6
PubMed Abstract | CrossRef Full Text | Google Scholar

efik E, Qu R, Junqueira C, Kaffe E, Mirza H, Zhao J, et al. Inflammasome activation in infected macrophages drives COVID-19 pathology. Nature (2022) 606(7914):585–93. doi: 10.1038/s41586-022-04802-1
PubMed Abstract | CrossRef Full Text | Google Scholar

Toldo S, Bussani R, Nuzzi V, Bonaventura A, Mauro AG, Cannatà A, et al. Inflammasome formation in the lungs of patients with fatal COVID-19. Inflammation Res (2021) 70(1):7–10. doi: 10.1007/s00011-020-01413-2
CrossRef Full Text | Google Scholar

Amin S, Aktar S, Rahman MM, Chowdhury MMH. NLRP3 inflammasome activation in COVID-19: an interlink between risk factors and disease severity. Microbes Infect (2022) 24(1):104913. doi: 10.1016/j.micinf.2021.104913
PubMed Abstract | CrossRef Full Text | Google Scholar

Braun J, Loyal L, Frentsch M, Wendisch D, Georg P, Kurth F, et al. SARS-CoV-2-reactive T cells in healthy donors and patients with COVID-19. Nature (2020) 587(7833):270–4. doi: 10.1038/s41586-020-2598-9
PubMed Abstract | CrossRef Full Text | Google Scholar

 Mathew D, Giles JR, Baxter AE, Oldridge DA, Greenplate AR, Wu JE, et al. Deep immune profiling of COVID-19 patients reveals distinct immunotypes with therapeutic implications. Science (2020) 369(6508):eabc8511. doi: 10.1126/science.369.6508.1203-l
PubMed Abstract | CrossRef Full Text | Google Scholar

Liu Y, Pan Y, Hu Z, Wu M, Wang C, Feng Z, et al. Thymosin alpha 1 reduces the mortality of severe coronavirus disease 2019 by restoration of lymphocytopenia and reversion of exhausted T cells. Clin Infect Dis (2020) 71(16):2150–7. doi: 10.1093/cid/ciaa630
PubMed Abstract | CrossRef Full Text | Google Scholar

Ren X, Wen W, Fan X, Hou W, Su B, Cai P, et al. COVID-19 immune features revealed by a large-scale single-cell transcriptome atlas. Cell (2021) 184(23):5838. doi: 10.1016/j.cell.2021.01.053
PubMed Abstract | CrossRef Full Text | Google Scholar

Xiang Q, Feng Z, Diao B, Tu C, Qiao Q, Yang H, et al. SARS-CoV-2 induces lymphocytopenia by promoting inflammation and decimates secondary lymphoid organs. Front Immunol (2021) 12:661052. doi: 10.3389/fimmu.2021.661052
PubMed Abstract | CrossRef Full Text | Google Scholar

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