Immunological aspects of COVID-19 pathogenesis: a review

Authors

DOI:

https://doi.org/10.56294/hl2024.461

Keywords:

immunology, COVID-19, SARS-CoV-2, infection

Abstract

Introduction: COVID-19, caused by SARS-CoV-2, has challenged the scientific and medical community since its emergence. Understanding the immunopathogenic events that occur during infection is crucial to developing effective treatment and prevention strategies.
Objective: To synthesize the immunological aspects in the pathogenesis of coronavirus disease 2019.
Development: SARS-CoV-2 infection begins with the entry of the virus into host cells through the ACE2 receptor. Once inside, the virus induces an immune response. In the early stages, the innate immune response is activated, which includes the release of interferons and cytokines. However, in some patients, this response becomes deregulated, triggering a cytokine storm that contributes to systemic inflammation and lung damage. T and B cells also play a crucial role; although the activation of CD8+ T cells can help control the infection, their depletion in severe cases has been associated with worse clinical outcomes. 
Conclusions: Immunopathogenic events in COVID-19 are complex and can lead to diverse clinical outcomes. Understanding these mechanisms is essential for the development of targeted therapies and effective vaccines. Continued research is critical to improving our response to future pandemics.

References

1. Hu B, Guo H, Zhou P, Shi Z-L. Characteristics of SARS-CoV-2 and COVID-19. Nat Rev Microbiol 2021;19:141-54. https://doi.org/10.1038/s41579-020-00459-7.

2. Yang L, Liu S, Liu J, Zhang Z, Wan X, Huang B, et al. COVID-19: immunopathogenesis and Immunotherapeutics. Sig Transduct Target Ther 2020;5:128. https://doi.org/10.1038/s41392-020-00243-2.

3. Diamond MS, Kanneganti T-D. Innate immunity: the first line of defense against SARS-CoV-2. Nat Immunol 2022;23:165-76. https://doi.org/10.1038/s41590-021-01091-0.

4. Feng Z, Diao B, Wang R, Wang G, Wang C, Tan Y, et al. The Novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Directly Decimates Human Spleens and Lymph Nodes 2020. https://doi.org/10.1101/2020.03.27.20045427.

5. Wiersinga WJ, Rhodes A, Cheng AC, Peacock SJ, Prescott HC. Pathophysiology, Transmission, Diagnosis, and Treatment of Coronavirus Disease 2019 (COVID-19): A Review. JAMA 2020;324:782. https://doi.org/10.1001/jama.2020.12839.

6. Sapir T, Averch Z, Lerman B, Bodzin A, Fishman Y, Maitra R. COVID-19 and the Immune Response: A Multi-Phasic Approach to the Treatment of COVID-19. IJMS 2022;23:8606. https://doi.org/10.3390/ijms23158606.

7. Teuwen L-A, Geldhof V, Pasut A, Carmeliet P. COVID-19: the vasculature unleashed. Nat Rev Immunol 2020;20:389-91. https://doi.org/10.1038/s41577-020-0343-0.

8. Ashraf UM, Abokor AA, Edwards JM, Waigi EW, Royfman RS, Hasan SA-M, et al. SARS-CoV-2, ACE2 expression, and systemic organ invasion. Physiological Genomics 2021;53:51-60. https://doi.org/10.1152/physiolgenomics.00087.2020.

9. Azkur AK, Akdis M, Azkur D, Sokolowska M, Van De Veen W, Brüggen M, et al. Immune response to SARS‐CoV‐2 and mechanisms of immunopathological changes in COVID‐19. Allergy 2020;75:1564-81. https://doi.org/10.1111/all.14364.

10. Xu G, Qi F, Li H, Yang Q, Wang H, Wang X, et al. The differential immune responses to COVID-19 in peripheral and lung revealed by single-cell RNA sequencing. Cell Discov 2020;6:73. https://doi.org/10.1038/s41421-020-00225-2.

11. Li Q, Wang Y, Sun Q, Knopf J, Herrmann M, Lin L, et al. Immune response in COVID-19: what is next? Cell Death & Differentiation 2022;29:1107-22.

12. Barreras Sixto D, Orraca Castillo O, Valdés Lanza L, Miló Valdés CA, Lugo Hernández A, Martínez Carmona Y. Aspectos clínicos-epidemiológicos de la COVID-19 en pacientes de Pinar del Río. Rev Ciencias Médicas 2022;26:e5486.

13. Van Der Sluis RM, Holm CK, Jakobsen MR. Plasmacytoid dendritic cells during COVID-19: Ally or adversary? Cell Reports 2022;40:111148. https://doi.org/10.1016/j.celrep.2022.111148.

14. Boumaza A, Gay L, Mezouar S, Bestion E, Diallo AB, Michel M, et al. Monocytes and Macrophages, Targets of Severe Acute Respiratory Syndrome Coronavirus 2: The Clue for Coronavirus Disease 2019 Immunoparalysis. The Journal of Infectious Diseases 2021;224:395-406. https://doi.org/10.1093/infdis/jiab044.

15. Luo X, Zhu Y, Mao J, Du R. T cell immunobiology and cytokine storm of COVID‐19. Scand J Immunol 2021;93:e12989. https://doi.org/10.1111/sji.12989.

16. Gagliardi MC, Tieri P, Ortona E, Ruggieri A. ACE2 expression and sex disparity in COVID-19. Cell Death Discov 2020;6:37. https://doi.org/10.1038/s41420-020-0276-1.

17. Ghosh A, Girish V, Yuan ML, Coakley RD, Alexis NE, Sausville EL, et al. Combustible and electronic cigarette exposures increase ACE2 activity and SARS-CoV-2 Spike binding. American Journal of Respiratory and Critical Care Medicine 2022;205. https://doi.org/10.1101/2021.06.04.447156.

18. Chang T, Yang J, Deng H, Chen D, Yang X, Tang Z-H. Depletion and Dysfunction of Dendritic Cells: Understanding SARS-CoV-2 Infection. Front Immunol 2022;13:843342. https://doi.org/10.3389/fimmu.2022.843342.

19. Jin Y, Yang H, Ji W, Wu W, Chen S, Zhang W, et al. Virology, Epidemiology, Pathogenesis, and Control of COVID-19. Viruses 2020;12:372. https://doi.org/10.3390/v12040372.

20. Knoll R, Schultze JL, Schulte-Schrepping J. Monocytes and Macrophages in COVID-19. Front Immunol 2021;12:720109. https://doi.org/10.3389/fimmu.2021.720109.

21. Paces J, Strizova Z, Smrz D, Cerny J. COVID-19 and the Immune System. Physiol Res 2020:379-88. https://doi.org/10.33549/physiolres.934492.

22. Schreiber G. The Role of Type I Interferons in the Pathogenesis and Treatment of COVID-19. Front Immunol 2020;11:595739. https://doi.org/10.3389/fimmu.2020.595739.

23. Wang X, Guan F, Miller H, Byazrova MG, Candotti F, Benlagha K, et al. The role of dendritic cells in COVID-19 infection. Emerging Microbes & Infections 2023;12:2195019. https://doi.org/10.1080/22221751.2023.2195019.

24. Eskandarian M, Sekrecka A, Antonczyk A, Hassani S, Sekrecki M, Nowicka H, et al. Dysregulated Interferon Response and Immune Hyperactivation in Severe COVID-19: Targeting STATs as a Novel Therapeutic Strategy. Front Immunol 2022;13:888897. https://doi.org/10.3389/fimmu.2022.888897.

25. Samuel CE. Interferon at the crossroads of SARS-CoV-2 infection and COVID-19 disease. Journal of Biological Chemistry 2023;299:104960. https://doi.org/10.1016/j.jbc.2023.104960.

26. Vardhana SA, Wolchok JD. The many faces of the anti-COVID immune response. Journal of Experimental Medicine 2020;217:e20200678. https://doi.org/10.1084/jem.20200678.

27. Maggi E, Canonica GW, Moretta L. COVID-19: Unanswered questions on immune response and pathogenesis. Journal of Allergy and Clinical Immunology 2020;146:18-22. https://doi.org/10.1016/j.jaci.2020.05.001.

28. Zafarani A, Razizadeh MH, Pashangzadeh S, Amirzargar MR, Taghavi-Farahabadi M, Mahmoudi M. Natural killer cells in COVID-19: from infection, to vaccination and therapy. Future Virology 2023;18:177-91. https://doi.org/10.2217/fvl-2022-0040.

29. Meidaninikjeh S, Sabouni N, Marzouni HZ, Bengar S, Khalili A, Jafari R. Monocytes and macrophages in COVID-19: Friends and foes. Life Sciences 2021;269:119010. https://doi.org/10.1016/j.lfs.2020.119010.

30. Tay MZ, Poh CM, Rénia L, MacAry PA, Ng LFP. The trinity of COVID-19: immunity, inflammation and intervention. Nat Rev Immunol 2020;20:363-74. https://doi.org/10.1038/s41577-020-0311-8.

31. Singh DK, Aladyeva E, Das S, Singh B, Esaulova E, Swain A, et al. Myeloid cell interferon responses correlate with clearance of SARS-CoV-2. Nat Commun 2022;13:679. https://doi.org/10.1038/s41467-022-28315-7.

32. Di Vito C, Calcaterra F, Coianiz N, Terzoli S, Voza A, Mikulak J, et al. Natural Killer Cells in SARS-CoV-2 Infection: Pathophysiology and Therapeutic Implications. Front Immunol 2022;13:888248. https://doi.org/10.3389/fimmu.2022.888248.

33. Darif D, Hammi I, Kihel A, El Idrissi Saik I, Guessous F, Akarid K. The pro-inflammatory cytokines in COVID-19 pathogenesis: What goes wrong? Microbial Pathogenesis 2021;153:104799. https://doi.org/10.1016/j.micpath.2021.104799.

34. Abel AM, Yang C, Thakar MS, Malarkannan S. Natural Killer Cells: Development, Maturation, and Clinical Utilization. Front Immunol 2018;9:1869. https://doi.org/10.3389/fimmu.2018.01869.

35. Kumar A, Cao W, Endrias K, Kuchipudi SV, Mittal SK, Sambhara S. Innate lymphoid cells (ILC) in SARS-CoV-2 infection. Molecular Aspects of Medicine 2021;80:101008. https://doi.org/10.1016/j.mam.2021.101008.

36. Wilk AJ, Rustagi A, Zhao NQ, Roque J, Martínez-Colón GJ, McKechnie JL, et al. A single-cell atlas of the peripheral immune response in patients with severe COVID-19. Nat Med 2020;26:1070-6. https://doi.org/10.1038/s41591-020-0944-y.

37. Silverstein NJ, Wang Y, Manickas-Hill Z, Carbone C, Dauphin A, Boribong BP, et al. Innate lymphoid cells and COVID-19 severity in SARS-CoV-2 infection. eLife 2022;11:e74681. https://doi.org/10.7554/eLife.74681.

38. Li J, Zhang K, Zhang Y, Gu Z, Huang C. Neutrophils in COVID-19: recent insights and advances. Virol J 2023;20:169. https://doi.org/10.1186/s12985-023-02116-w.

39. McKenna E, Wubben R, Isaza-Correa JM, Melo AM, Mhaonaigh AU, Conlon N, et al. Neutrophils in COVID-19: Not Innocent Bystanders. Front Immunol 2022;13:864387. https://doi.org/10.3389/fimmu.2022.864387.

40. Licari A, Votto M, Brambilla I, Castagnoli R, Piccotti E, Olcese R, et al. Allergy and asthma in children and adolescents during the COVID outbreak: What we know and how we could prevent allergy and asthma flares. Allergy 2020;75:2402-5. https://doi.org/10.1111/all.14369.

41. Kanannejad Z, Alyasin S, Esmaeilzadeh H, Nabavizadeh H, Amin R. Asthma and COVID-19 pandemic: focus on the eosinophil count and ACE2 expression. Eur Ann Allergy Clin Immunol 2022;54:284. https://doi.org/10.23822/EurAnnACI.1764-1489.233.

42. Lindsley AW, Schwartz JT, Rothenberg ME. Eosinophil responses during COVID-19 infections and coronavirus vaccination. Journal of Allergy and Clinical Immunology 2020;146:1-7. https://doi.org/10.1016/j.jaci.2020.04.021.

43. Rosenberg HF, Foster PS. Eosinophils and COVID-19: diagnosis, prognosis, and vaccination strategies. Semin Immunopathol 2021;43:383-92. https://doi.org/10.1007/s00281-021-00850-3.

44. Kalfaoglu B, Almeida-Santos J, Tye CA, Satou Y, Ono M. T-cell dysregulation in COVID-19. Biochemical and Biophysical Research Communications 2021;538:204-10. https://doi.org/10.1016/j.bbrc.2020.10.079.

45. Sosa JP, Ferreira Caceres MM, Ross Comptis J, Quiros J, Príncipe-Meneses FS, Riva-Moscoso A, et al. Effects of Interferon Beta in COVID-19 adult patients: Systematic Review. Infect Chemother 2021;53:247. https://doi.org/10.3947/ic.2021.0028.

46. Huang L, Shi Y, Gong B, Jiang L, Zhang Z, Liu X, et al. Dynamic blood single-cell immune responses in patients with COVID-19. Sig Transduct Target Ther 2021;6:110. https://doi.org/10.1038/s41392-021-00526-2.

47. Trouillet-Assant S, Viel S, Gaymard A, Pons S, Richard J-C, Perret M, et al. Type I IFN immunoprofiling in COVID-19 patients. Journal of Allergy and Clinical Immunology 2020;146:206-208.e2. https://doi.org/10.1016/j.jaci.2020.04.029.

48. Stephenson E, Reynolds G, Botting RA, Calero-Nieto FJ, Morgan MD, Tuong ZK, et al. Single-cell multi-omics analysis of the immune response in COVID-19. Nat Med 2021;27:904-16. https://doi.org/10.1038/s41591-021-01329-2.

49. Stokel-Walker C. What do we know about the adaptive immune response to covid-19? BMJ 2023:p19.

50. Medina-Enríquez MM, Lopez-León S, Carlos-Escalante JA, Aponte-Torres Z, Cuapio A, Wegman-Ostrosky T. ACE2: the molecular doorway to SARS-CoV-2. Cell Biosci 2020;10:148. https://doi.org/10.1186/s13578-020-00519-8.

51. Koblischke M, Traugott MT, Medits I, Spitzer FS, Zoufaly A, Weseslindtner L, et al. Dynamics of CD4 T Cell and Antibody Responses in COVID-19 Patients With Different Disease Severity. Front Med 2020;7:592629. https://doi.org/10.3389/fmed.2020.592629.

52. Westmeier J, Paniskaki K, Karaköse Z, Werner T, Sutter K, Dolff S, et al. Impaired Cytotoxic CD8+ T Cell Response in Elderly COVID-19 Patients. mBio 2020;11:e02243-20. https://doi.org/10.1128/mBio.02243-20.

53. Bean J, Kuri-Cervantes L, Pennella M, Betts MR, Meyer NJ, Hassan WM. Multivariate indicators of disease severity in COVID-19. Scientific Reports 2023:5145.

54. Moss P. The T cell immune response against SARS-CoV-2. Nat Immunol 2022;23:186-93. https://doi.org/10.1038/s41590-021-01122-w.

55. Odak I, Barros-Martins J, Bošnjak B, Stahl K, David S, Wiesner O, et al. Reappearance of effector T cells is associated with recovery from COVID-19. EBioMedicine 2020;57:102885. https://doi.org/10.1016/j.ebiom.2020.102885.

56. Tian Y, Carpp LN, Miller HER, Zager M, Newell EW, Gottardo R. Single-cell immunology of SARS-CoV-2 infection. Nat Biotechnol 2022;40:30-41. https://doi.org/10.1038/s41587-021-01131-y.

57. Zhang J-Y, Wang X-M, Xing X, Xu Z, Zhang C, Song J-W, et al. Single-cell landscape of immunological responses in patients with COVID-19. Nat Immunol 2020;21:1107-18. https://doi.org/10.1038/s41590-020-0762-x.

58. Zhao X-N, You Y, Cui X-M, Gao H-X, Wang G-L, Zhang S-B, et al. Single-cell immune profiling reveals distinct immune response in asymptomatic COVID-19 patients. Sig Transduct Target Ther 2021;6:342. https://doi.org/10.1038/s41392-021-00753-7.

59. Shrotri M, Van Schalkwyk MCI, Post N, Eddy D, Huntley C, Leeman D, et al. T cell response to SARS-CoV-2 infection in humans: A systematic review. PLoS ONE 2021;16:e0245532. https://doi.org/10.1371/journal.pone.0245532.

60. Gupta A, Chander Chiang K. Prostaglandin D2 as a mediator of lymphopenia and a therapeutic target in COVID-19 disease. Medical Hypotheses 2020;143:110122. https://doi.org/10.1016/j.mehy.2020.110122.

61. Mahmoudi S, Rezaei M, Mansouri N, Marjani M, Mansouri D. Immunologic Features in Coronavirus Disease 2019: Functional Exhaustion of T Cells and Cytokine Storm. J Clin Immunol 2020;40:974-6. https://doi.org/10.1007/s10875-020-00824-4.

62. Ganji A, Farahani I, Khansarinejad B, Ghazavi A, Mosayebi G. Increased expression of CD8 marker on T-cells in COVID-19 patients. Blood Cells, Molecules, and Diseases 2020;83:102437. https://doi.org/10.1016/j.bcmd.2020.102437.

63. Mohammed RN, Tamjidifar R, Rahman HS, Adili A, Ghoreishizadeh S, Saeedi H, et al. A comprehensive review about immune responses and exhaustion during coronavirus disease (COVID-19). Cell Commun Signal 2022;20:79. https://doi.org/10.1186/s12964-022-00856-w.

64. Ahmadpoor P, Rostaing L. Why the immune system fails to mount an adaptive immune response to a COVID‐19 infection. Transpl Int 2020;33:824-5. https://doi.org/10.1111/tri.13611.

65. Hosseini A, Esmaeili Gouvarchin Ghaleh H, Aghamollaei H, Fasihi Ramandi M, Alishiri G, Shahriary A, et al. Evaluation of Th1 and Th2 mediated cellular and humoral immunity in patients with COVID-19 following the use of melatonin as an adjunctive treatment. European Journal of Pharmacology 2021;904:174193. https://doi.org/10.1016/j.ejphar.2021.174193.

66. Gupta G, Shareef I, Tomar S, Kumar MSN, Pandey S, Sarda R, et al. Th1/Th2/Th17 Cytokine Profile among Different Stages of COVID-19 Infection. Natl Acad Sci Lett 2022;45:363-9. https://doi.org/10.1007/s40009-022-01123-9.

67. Martonik D, Parfieniuk-Kowerda A, Rogalska M, Flisiak R. The Role of Th17 Response in COVID-19. Cells 2021;10:1550. https://doi.org/10.3390/cells10061550.

68. Hackenbruch C, Maringer Y, Tegeler CM, Walz JS, Nelde A, Heitmann JS. Elevated SARS-CoV-2-Specific Antibody Levels in Patients with Post-COVID Syndrome. Viruses 2023;15:701. https://doi.org/10.3390/v15030701.

69. Yu K, He J, Wu Y, Xie B, Liu X, Wei B, et al. Dysregulated adaptive immune response contributes to severe COVID-19. Cell Res 2020;30:814-6. https://doi.org/10.1038/s41422-020-0391-9.

70. Qi H, Liu B, Wang X, Zhang L. The humoral response and antibodies against SARS-CoV-2 infection. Nat Immunol 2022;23:1008-20. https://doi.org/10.1038/s41590-022-01248-5.

71. Ngo HT, Tran SV, Nguyen HD, Truong PQ. Humoral immune response in COVID-19 patients and novel design of lateral flow assay strip for simultaneous rapid detection of IgA/IgM/ IgG antibodies against the SARS-CoV-2 virus. J App Biol Biotech 2023;11:102-13. https://doi.org/10.7324/JABB.2023.110209.

72. Liu X, Wang J, Xu X, Liao G, Chen Y, Hu C-H. Patterns of IgG and IgM antibody response in COVID-19 patients. Emerging Microbes & Infections 2020;9:1269-74. https://doi.org/10.1080/22221751.2020.1773324.

73. Mason RJ. Pathogenesis of COVID-19 from a cell biology perspective. Eur Respir J 2020;55:2000607. https://doi.org/10.1183/13993003.00607-2020.

74. Nile SH, Nile A, Qiu J, Li L, Jia X, Kai G. COVID-19: Pathogenesis, cytokine storm and therapeutic potential of interferons. Cytokine & Growth Factor Reviews 2020;53:66-70. https://doi.org/10.1016/j.cytogfr.2020.05.002.

75. Gibellini L, De Biasi S, Meschiari M, Gozzi L, Paolini A, Borella R, et al. Plasma Cytokine Atlas Reveals the Importance of TH2 Polarization and Interferons in Predicting COVID-19 Severity and Survival. Front Immunol 2022;13:842150. https://doi.org/10.3389/fimmu.2022.842150.

76. Shi C, Cao P, Wang Y, Zhang Q, Zhang D, Wang Y, et al. PANoptosis: A Cell Death Characterized by Pyroptosis, Apoptosis, and Necroptosis. JIR 2023;Volume 16:1523-32. https://doi.org/10.2147/JIR.S403819.

77. Choudhary S, Sharma K, Silakari O. The interplay between inflammatory pathways and COVID-19: A critical review on pathogenesis and therapeutic options. Microbial Pathogenesis 2021;150:104673. https://doi.org/10.1016/j.micpath.2020.104673.

78. Conti P, Ronconi G, Caraffa A, Gallenga CE, Ross R, Frydas I, et al. Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by COVID-19: anti-inflammatory strategies. J Biol Regul Homeost Agents 2020;34:11-5. https://doi.org/10.23812/CONTI-E.

79. Gan R, Rosoman NP, Henshaw DJE, Noble EP, Georgius P, Sommerfeld N. COVID-19 as a viral functional ACE2 deficiency disorder with ACE2 related multi-organ disease. Medical Hypotheses 2020;144:110024. https://doi.org/10.1016/j.mehy.2020.110024.

Downloads

Published

2024-12-31

How to Cite

1.
Miló Valdés CA, Pérez Acevedo LC. Immunological aspects of COVID-19 pathogenesis: a review. Health Leadership and Quality of Life [Internet]. 2024 Dec. 31 [cited 2025 Aug. 24];3:.461. Available from: https://hl.ageditor.ar/index.php/hl/article/view/461