|Year : 2020 | Volume
| Issue : 1 | Page : 23-27
Covid-19 immune mechanisms: A systematic review
Shalini Gandhi1, Sandeep Kumar Sharma2, Purva Shoor3, Jitender Sorout4, Abhay Raina5, Rohit Raina6, Urvashi Miglani7, Uma Kant Chaudhari2, Shivi Srivastava4
1 Department of Physiology, KD Medical College, Hospital and Research Center, Mathura, Uttar Pradesh, India
2 Department of Biochemistry, KD Medical College, Mathura, Uttar Pradesh, India
3 Department of Community Medicine, KD Medical College, Mathura, Uttar Pradesh, India
4 Department of Physiology, KD Medical College, Mathura, Uttar Pradesh, India
5 Krishna Scan Center, Cuddalore, Tamil Nadu, India
6 Department of Radiology, Indraprastha Apollo Hospital, New Delhi, India
7 Department of Obstetrics and Gynaecology, Deen Dayal Upadhyay Hospital, Delhi, India
|Date of Submission||14-May-2020|
|Date of Acceptance||08-Jun-2020|
|Date of Web Publication||6-Jul-2020|
Dr. Sandeep Kumar Sharma
Department of Biochemistry, First Floor, Academic Block, KD Medical College Campus, Akbarpur, Mathura-Delhi Highway, Mathura - 281 406, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
There is a new public health crises threatening globally with the emergence and spread of 2019 novel coronavirus or the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It is the seventh member of the coronavirus (CoV) family, which infects humans and to which the Middle East Respiratory Syndrome CoV (MERS)-and SARS-CoV also belong. SARS-CoV-2 is a newly emerging human infectious CoV that causes COVID-19, which has been recognized as a pandemic by the World Health Organization on March 11. The most recent outbreak initially presented as pneumonia of unknown etiology as COVID-19 is a pneumonia-like disease with a group of symptoms including fever, dry cough and shortness of breath in a cluster of patients in December 2019 Wuhan, China. The body's immune system tries to protect the body from this pathogen. And as due to its surge in the body, various respiratory and other system-related complications increased. Therefore, in this article, COVID-19 immunopathogenesis is briefly reviewed. Through this review, we try to explain the molecular immune pathogenesis and diagnosis of COVID-19 (SARS-CoV-2) infection, based on the recent research progress of SARS-CoV-2 and the knowledge from researches on SARS-CoV and MERS-CoV.
Keywords: Immunopathogenesis, Middle East Respiratory Syndrome Coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2, Severe Acute Respiratory Syndrome Coronavirus
|How to cite this article:|
Gandhi S, Sharma SK, Shoor P, Sorout J, Raina A, Raina R, Miglani U, Chaudhari UK, Srivastava S. Covid-19 immune mechanisms: A systematic review. Indian J Allergy Asthma Immunol 2020;34:23-7
|How to cite this URL:|
Gandhi S, Sharma SK, Shoor P, Sorout J, Raina A, Raina R, Miglani U, Chaudhari UK, Srivastava S. Covid-19 immune mechanisms: A systematic review. Indian J Allergy Asthma Immunol [serial online] 2020 [cited 2020 Nov 30];34:23-7. Available from: https://www.ijaai.in/text.asp?2020/34/1/23/289062
| Introduction|| |
From January 2020, coronavirus disease (COVID-19) has spread fast from China, mainly to Southwest Asia and Europe, especially to Italy, and it is now found everywhere around the world. The disease is caused by Severe Acute Respiratory Syndrome CoV 2 (SARS-CoV-2), the seventh member of the CoV family, which infects humans and to which Middle East Respiratory Syndrome CoV (MERS)-CoV and SARS-CoV also belong. The classical clinical picture of COVID19 is that of a flu-like syndrome of mild severity in most cases, but in 15% of cases, it is complicated by interstitial pneumonia and a variable degree of respiratory failure. Novel CoV (nCoV)-induced pneumonia, which was named as CoV disease 2019 (COVID-19) by the World Health Organization (WHO) on February 11, 2020, has rapidly increased in epidemic scale since it first appeared in Wuhan, China, in December 2019. On the January 31, 2020, the WHO announced that COVID-19 was listed as the Public Health Emergency of International Concern, meaning that it may pose risks to multiple countries and requires a coordinated international response. Patients with COVID-19 show clinical manifestations including fever, nonproductive cough, dyspnea, myalgia, fatigue, normal or decreased leukocyte counts, and radiographic evidence of pneumonia, which are similar to the symptoms of SARS-CoV and MERS-CoV infections., Through this review, we try to explain the molecular immune pathogenesis and diagnosis of COVID-19 (SARS-CoV-2) infection, based on the recent research progress of SARS-CoV-2 and the knowledge from researches on SARS-CoV and MERS-CoV.
| Research Methodology|| |
On April 19, 2020, we searched Pubmed Central and Google Scholar for relevant articles. Full-text articles were downloaded dated December 2019 to April 19, 2020. Relevance was judged according to articles describing theories of immune-mechanisms influencing the Covid-19 pandemic. We carried out in-depth literature review, scrutinizing every article out of total results following a search by key words. One article published in 2006 was also included.
First, we searched Google Scholar with key words “Immune mechanism in Covid-19”. 4 relevant articles were downloaded of which 1 article was a journal pre-proof.
Second, we searched Pubmed Central with key words:
- Immune mechanisms in COVID-19: We obtained 426 results of which 37 relevant articles were downloaded from pages 1-10 and 5 relevant articles were downloaded from pages 11–22
- Immune-pathology of Covid-19 patients: We obtained 215 results of which 25 relevant researches were duplicates of search a, and 1 pre-proof article was downloaded
- Variable immune-pathology pattern in COVID-19 patients: We obtained two duplicate relevant articles downloaded from search a. out of 20 results
- Pattern of immune pathology in Covid-19 patients: Out of 92 results, there were seven duplicate relevant articles with search a.
Therefore, total relevant articles included in this narrative review are 47.
Distinct features of novel corona virus in comparison to previous epidemics
The first CoV was isolated in 1930 and was called the “Avian Infectious Bronchitis.” After this event, several other subtypes were isolated from rodents, domestic animals including mouse, pig, cow, turkey, cats, whales, and dogs. The first human strain was discovered from the clinical specimen of patients with the common cold. This strain was B814 isolated in 1962. There were six CoVs known to cause disease in humans. The viruses known as human CoV (hCoV)-229E, hCoV-HKU1, hCoV-NL63 (was associated with viral croup in children), and hCoV-OC43 were of little concern at a global public health level. In the 1960s, 229E and OC43 were etiological agents for 30% of common colds., CoV genome is approximately 30kb long, thereby known as the longest RNA virus. The other two out of six human viruses were of the epidemic level. Of them, MERS-CoV had shown limited human-to-human transmission than SARS-CoV, but both these viral infections were found to be highly pathogenic and fatal. The present pandemic, SARS-CoV-2 is the seventh hCoV.,,
CoVs include both protein and sugar receptors. They first attach to a host cell surface receptor, then fuse together viral and host membrane for entry. They recognize a variety of receptors using their spike protein. Receptor Binding weakens the interaction between Spike protein 1 and 2. This dissociation leads from pre-fusion to post-fusion conformation.
The structural proteins stabilize the virus particle. They are the spike protein S and Nucleocapsid protein N. The N protein enables transcription and assembly efficiency of the virus. The spike protein binds to cellular receptors and mediates infection and replication of the virus in host cells. According to Weiss SR, SARS CoV-2 spike protein has a furin cleavage site in the S1-S2 junction that is different from SARS-CoV. The new furin site can become a marker to detect the precursor of this virus.
One of the earliest receptors for CoV was discovered in 1991 for Mouse Hepatic Virus from the Carcinoembryonic antigen family (CEACAM1a). Later, as described in [Table 1], ACE2 receptors were recognized for SARS-CoV and DPP4 for MERS-CoV. It is also postulated that ACE2 is the receptor for attachment of nCoV, although it only had 79.5% genome sequence similarity to SARS-CoV., Binding to Integrin protein is supplementary to ACE2 binding, to facilitate endocytosis in even other target cells by either or both ACE2 and Integrin receptors.
|Table 1: Distinct characteristics of severe Coronavirus epidemics in the past 20 years|
Click here to view
Virulence factors that contribute to pathogenesis are not only the spike protein. Other background genes, nucleocapsid, and replicase are involved in viral tropism. A study identified two specific epitopes on SARS-CoV spike protein, 447-458 and 789-799. When these epitopes were compared with the spike protein of SARS-CoV-2, they found 72.7% and 100% homology, respectively, for the two epitopes. Vaccine generation can occur if Spike proteins are exploited as candidates. N protein is the most abundant protein in CoVs, but does not change through convergence or divergence. It shares 90% identity with SARS-CoV, through which we can imply that antibodies to the former SARS recognize and bind to nCoV though it does not provide immunity. This fact has enabled us to use serum-based assays to detect asymptomatic Covid-19 cases.
Early studies indicated that the new virus was genetically similar to a bat beta-CoV, the third human infecting CoV in the past 20 years. According to Kumar et al., “there was a notable difference in the longer spike protein of 2019-nCoV when compared with the bat SARS-like CoVs and SARS-CoV. Further, complete sequence alignment data suggested that spike glycoprotein sequences of nCoV and SARS-CoV exhibit 76.2% identity, 87.2% similarity, and 2% Gaps. The significant variation in minimal Receptor Binding Domain of S-glycoprotein suggests that nCoV may have alteration in virus binding capacity and infectivity into the host cell receptor. There is an insignificant divergence in spike protein when SARS-CoV is compared with nCoV.,,” Hence the SARS-CoV-2 virus is similar to its two predecessors like SARS-CoV and MERS-CoV antigenically. Furthermore, the pathogenicity and fatality of nCov are attenuated due to evolution and its adaptation to human cells. Fung et al. propounds that CoVs have existed for the past 6000 years. Although most hCoVs retain one or other characteristics to counter host antiviral defense, due to which they may sabotage the host's immune system drastically, this capability is lost once they adapt to human cells.
| Immunopathology|| |
Invasion into host cells by severe acute respiratory syndrome corona virus 2-mechanism
The life cycle of the virus with the host consists of the following five steps: attachment, penetration, biosynthesis, maturation, and release. Once viruses bind to host receptors (attachment), they enter host cells through endocytosis or membrane fusion (penetration). Once viral contents are released inside the host cells, viral RNA enters the nucleus for replication. Viral mRNA is used to make viral proteins (biosynthesis). Then, new viral particles are made (maturation) and released. CoVs consist of four structural proteins; Spike (S), membrane (M), envelop (E), and nucleocapsid (N). Angiotensin-converting enzyme 2 (ACE2) was identified as a functional receptor for SARS-CoV. A two-step sequential protease cleavage to activate spike protein of SARS-CoV and MERS-CoV was proposed as a model, consisting of cleavage at the S1/S2 cleavage site for priming and cleavage for activation at the S2 site, a position adjacent to a fusion peptide within the S2 subunit.,, Cleavage at the S2 site presumably activates the spike for membrane fusion through irreversible, conformational changes. The CoV spike is unusual among viruses because a range of different proteases can cleave and activate it.
Response of host against severe acute respiratory syndrome corona virus 2
The symptom of patients infected with SARS-CoV-2 ranges from minimal symptoms to severe respiratory failure with multiple organ failure. On the computerized tomography scan, the characteristic pulmonary ground-glass opacification can be seen even in asymptomatic patients. Because ACE2 is highly expressed on the apical side of lung epithelial cells in the alveolar space,, this virus can likely enter and destroy them. T cell-mediated responses against CoVs have been previously reviewed. T cell responses are initiated by antigen presentation through DCs and macrophages. How does SARS-CoV-2 enter APCs? DCs and macrophages can phagocytize apoptotic cells infected by virus. ARS-CoV can also bind to dendritic-cell specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) and DC-SIGN-related protein (DC-SIGNR, L-SIGN) in addition to ACE2.,, Antigen-presenting cells move to the draining lymph nodes to present viral antigens to T-cells. CD4+ and CD8+ T-cells play a critical role. CD4+ T-cells activate B-cells to promote the production of virus-specific antibodies, while CD8+ T-cells can kill virally infected cells.
Patients with severe diseases showed lymphopenia, particularly the reduction in peripheral blood T-cells., Patients with severe diseases were reported to have increased plasma concentrations of proinflammatory cytokines, including interleukin (IL)-6, IL-10, granulocyte-colony stimulating factor (G-CSF), monocyte chemoattractant protein 1, macrophage inflammatory protein 1α, and tumor necrosis factor-α.,, The more severe conditions patients were in, the higher their IL-6 levels were. CD4+ and CD8+ T-cells were activated in those patients as suggested by higher expression of CD69, CD38 and CD44. Another interesting finding was that aberrant pathogenic CD4+ T cells with co-expressing interferon-γ and granulocyte-macrophage CSF were seen in COVID-19 patients with severe disease., The study of SARS-CoV showed that virus-infected lung epithelial cells produced IL-8 in addition to IL-6. IL-8 is a well-known chemoattractant for neutrophils and T-cells. Infiltration of a large number of inflammatory cells were observed in the lungs from severe COVID-19 patients,, and these cells presumably consist of a constellation of innate immune cells and adaptive immune cells. Among innate immune cells, we expect the majority to be neutrophils. Neutrophils can act as double-edged sword as neutrophils can induce lung injury.,, Overall, COVID-19 infection showed increased levels of plasma proinflammatory mediators., As in protective immunity is harming the body in this battle. These complications lead to respiratory distress syndrome and may potentially lead to death.
| Conclusion|| |
SARS-CoV-2 and the previous endemic outbreak of SARS and MERS, a similarity emerges with some special features of its own. COVID-19 responsible for various serious public health problems across Asia and the world population. The most recent outbreak initially presented as pneumonia of unknown etiology as COVID-19 is a pneumonia-like disease with a group of symptoms including fever, dry cough and shortness of breath in a cluster of patients Thus investigations into the features of SARS-CoV-2 and its interaction with the host immune responses may be helpful in providing a clear image of how this new unwanted guest (pathogen) causes diseases in some people, while some other infected people show mild symptoms. In the end, this study may be helpful in designing prophylactic and treatment measures for current and future outbreak of similar CoVs.
We would like to thank all the health-care professionals working to treat COVID patients. We also extend our best wishes to the police department and the Indian army for their brave fight against COVID-19 pandemic.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al
. A novel coronavirus from patients with pneumonia in China, 2019. N
Engl J Med 2020;382:727-33.
Rapezzi C, Ferrari R. The cardiologist at the time of coronavirus: A perfect storm. Eur Heart J 2020;41:1320-2.
Zhou P, Yang XL, Wang XG, Hu Ben, Zhang L, Zhang W, et al
. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020;579:270-3. doi: 10.1038/s41586-020-2012-7
Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al
. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China, Lancet 2020;395:497-506.
Peiris JS, Guan Y, Yuen KY. Severe acute respiratory syndrome. Nat Med 2004;10:S88eS97.22.
Taubenberger JK, Morens DM. 1918 Influenza: The mother of all pandemics. Emerg Infect Dis 2006;12:15-22.
Wei X, Li X, Cui J. Evolutionary perspectives on novel coronaviruses identified in pneumonia cases in China. Natl Sci Rev 2020;7:239-42.
Fung SY, Yuen KS, Ye ZW, Chan CP, Jin DY. A tug-of-war between severe acute respiratory syndrome coronavirus 2 and host antiviral defence: Lessons from other pathogenic viruses. Emerg Microbes Infect 2020;9:558-70.
Weston S, Frieman MB. COVID-19: Knowns, Unknowns, and Questions. mSphere 2020;5:e00203-20.
Xu J, Zhao S, Teng T, Abdalla AE, Zhu W, Xie L, et al
. Systematic Comparison of Two Animal-to-Human Transmitted Human Coronaviruses: SARS-CoV-2 and SARS-CoV. Viruses 2020;12:244. doi: 10.3390/v12020244.
Shang J, Wan Y, Liu C, Yount B, Gully K, Yang Y, et al
. Structure of mouse coronavirus spike protein complexed with receptor reveals mechanism for viral entry. PLoS Pathog 2020;16:e1008392.
Google Search: Corona Cases in the World. Covid-19 Alert Statistics. Time: 18 hrs 15 Minutes.
Prompetchara E, Ketloy C, Palaga T. Immune responses in COVID-19 and potential vaccines: Lessons learned from SARS and MERS epidemic. Asian Pac J Allergy Immunol 2020;38:1-9.
Tetro JA. Is COVID-19 receiving ADE from other coronaviruses? Microbes Infect 2020;22:72-3.
Sigrist CJ, Bridge A, Le Mercier P. A potential role for integrins in host cell entry by SARS-CoV-2. Antiviral Res 2020;177:104759.
Kumar S, Maurya VK, Prasad AK, Bhatt MLB, Saxena SK. Structural, glycosylation and antigenic variation between 2019 novel coronavirus (2019-nCoV) and SARS coronavirus (SARS-CoV). Virusdisease 2020;31:13-21.
Bosch BJ, van der Zee R, de Haan CA, Rottier PJ. The coronavirus spike protein is a class I virus fusion protein: Structural and functional characterization of the fusion core complex. Journal 2003;77:8801-11.
Li W, Moore MJ, Vasilieva N, Sui J, Wong SK, Berne MA, et al
. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature 2003;426:450-4.
Chen Y, Guo Y, Pan Y, Zhao ZJ. Structure analysis of the receptor binding of 2019-nCoV. Science Direct 2020;525:135-40.
Walls AC, Park YJ, Tortorici MA, Wall A, McGuire AT, Veesler D. Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell 2020;18:281-92.e6.
Letko M, Marzi A, Munster V. Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses. Nat Microbiol 2020;5:562-9.
Zou X, Chen K, Zou J, Han P, Hao J, Han Z. Single cell RNA seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019 nCoV infection. Front Med 2020;14:185-92.
Belouzard S, Chu VC, Whittaker GR. Activation of the SARS coronavirus spike protein via sequential proteolytic cleavage at two distinct sites. Proc Natl Acad Sci U S A 2009;106:5871-6.
Millet JK, Whittaker GR. Host cell entry of Middle East respiratory syndrome coronavirus after two-step, furin-mediated activation of the spike protein. Proc Natl Acad Sci U S A 2014;111:15214-9.
Ou X, Liu Y, Lei X, Li P, Mi D, Ren L, et al
. Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV. Nat Commun 2020;11:1620.
Belouzard S, Millet JK, Licitra BN, Whittaker GR. Mechanisms of coronavirus cell entry mediated by the viral spike protein. Viruses 2012;4:1011-33.
Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al
. China medical treatment expert group for clinical characteristics of coronavirus disease 2019 in China. N
Engl J Med 2020;382:1708-20. DOI: 10.1056/NEJMoa2002032.
Hamming I, Timens W, Bulthuis ML, Lely AT, Navis G, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol 2004;203:631-7.
Jia HP, Look DC, Shi L, Hickey M, Pewe L, Netland J, et al
. ACE2 receptor expression and severe acute respiratory syndrome coronavirus infection depend on differentiation of human airway epithelia. Journal 2005;79:14614-21.
Channappanavar R, Zhao J, Perlman S. T cell-mediated immune response to respiratory coronaviruses. Journal 2014;59:118-28.
Fujimoto I, Pan J, Takizawa T, Nakanishi Y. Virus clearance through apoptosis-dependent phagocytosis of influenza A virus-infected cells by macrophages. J Virol 2000;74:3399-403.
Jeffers SA, Tusell SM, Gillim-Ross L, Hemmila EM, Achenbach JE, Babcock GJ, et al
. CD209L (L-SIGN) is a receptor for severe acute respiratory syndrome coronavirus. Journal 2004;101:15748-53.
Marzi A, Gramberg T, Simmons G, Moller P, Rennekamp AJ, Krumbiegel M, et al
. DC-SIGN and DC-SIGNR interact with the glycoprotein of Marburg virus and the S protein of severe acute respiratory syndrome coronavirus. Journal 2004;78:12090-5.
Yang ZY, Huang Y, Ganesh L, Leung K, Kong WP, Schwartz O, et al
. pH-dependent entry of severe acute respiratory syndrome coronavirus is mediated by the spike glycoprotein and enhanced by dendritic cell transfer through DC-SIGN. J Virol 2004;78:5642-50.
Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al
. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395:497-506.
Zhou Y, Fu B, Zheng X, Wnag D, Zhao C, Qi Y, et al
. Pathogenic T cells and inflammatory monocytes incite inflammatory storm in severe COVID-19 patients. Natl Sci Rev 2020. doi: 10.1093/nsr/nwaa041. PMCID: PMC7108005.
Huang KJ, Su IJ, Theron M, Wu YC, Lai SK, Liu CC, et al
. An interferon-gamma-related cytokine storm in SARS patients. J Med Virol 2005;75:185-94.
Qin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y, et al
. Dysregulation of immune response in patients with COVID-19 in Wuhan, China. Clin Infect Dis 2020;ciaa248. doi:10.1093/cid/ciaa248.
Yoshikawa T, Hill T, Li K, Peters CJ, Tseng CT. Severe acute respiratory syndrome (SARS) coronavirus-induced lung epithelial cytokines exacerbate SARS pathogenesis by modulating intrinsic functions of monocyte-derived macrophages and dendritic cells. Journal 2009;83:3039-48.
Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, et al
. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Journal 2020;8:420-2.
Tian S, Hu W, Niu L, Liu H, Xu H, Xiao SY. Pulmonary pathology of Early-phase 2019 Novel Coronavirus (COVID-19) pneumonia in two patients with lung cancer. J Thorac Oncol 2020;15:700-704. doi: 10.1016/j.jtho.2020.02.010.
Young RE, Thompson RD, Larbi KY, La M, Roberts CE, Shapiro SD, et al
. Neutrophil elastase (NE)-deficient mice demonstrate a nonredundant role for NE in neutrophil migration, generation of proinflammatory mediators, and phagocytosis in response to zymosan particles in vivo
. J Immunol 2004;172:4493-502.
Liu S, Su X, Pan P, Zhang L, Hu Y, Tan H, et al
. Neutrophil extracellular traps are indirectly triggered by lipopolysaccharide and contribute to acute lung injury. Sci Rep 2016;6:37252.
Rothan HA, Byrareddy SN. The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak. J Autoimmun 2020;109:102433.
Nicholls JM, Poon LL, Lee KC, Ng WF, Lai ST, Leung CY, et al
. Lung pathology of fatal severe acute respiratory syndrome. Lancet 2003;361:1773-8.