COVID-19 & SARS-CoV-2: Immune Response & Mechanical Insights - Gao Y, Akdis C, et. al. (Publsihed 2022)

COVID-19 and SARS-CoV-2: Immune Response & Mechanistic Insights

Yadong Gao1, Mei Ding1, Xiang Dong1, Yuanli Sun1, Jinjin zhang1, Mubeccel Akdis2, Cezmi A Akdis2

  1. Department of Allergology, Zhongnan Hospital of Wuhan University. Donghu Road 169, Wuhan 430071, Hubei, P.R. China
  2. Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Switzerland. Herman-Burchard Strasse 9, 7265, Davos Wolfgang, Switzerland


Epidemiology and clinical characteristics of COVID-19

The pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused an unprecedented global social and economic impact, and numerous deaths. On 12 October 2020, COVID-19 pandemic reached over 5.1 million confirmed cases and claimed the lives of more than 1.2 million people worldwide. 220 countries reported cases of COVID-19 (WHO report)1.

SARS-CoV-2 was identified in airway epithelial cells from patients with unknown pneumonia2. Phylogenetic analysis showed that this virus belongs to subgenus sarbecovirus, Orthocoronavirinae subfamily and is more similar to two bat-derived coronavirus strains, bat-SL-CoVZC45 and bat-SL-CoVZXC21, than SAR-CoV 2,3. Angiotensin converting enzyme (ACE) 2 is the entry receptor for SARS-CoV-23. SARS-CoV-2 bins to ACE2 via its spike protein to enter human cells and this process is facilitated by the host serine protease TMPRSS2 that cleaves the spike protein into S1 and S2 fragments, thus enabling cellular membrane fusion4.

ACE2 is highly expressed in the lungs, small intestine, kidney and heart, but not in innate and adaptive immune cells5. SARS-CoV-2 also binds to CD147 (basigin, BSG, or extracellular matrix metalloproteinase inducer), which is expressed in human airway and kidney epithelium, as well as in innate cells and lymphocytes. Receptors such as CD26 (DPP4), aminopeptidase N and glutamyl aminopeptidase, could be utilized by SARS-CoV-2 for cell invasion5. ACE2 and TMPRESS2 expression was also confirmed in nasal and bronchial epithelial cells6,7

SARS-CoV-2 can be transmitted among population via respiratory droplets and aerosols. Fecal transmission of SARS-CoV-2 is possible and might contribute to the spreading of COVID-198. Elderly individuals and those with preexisting comorbidities such as hypertension, diabetes, chronic respiratory disease, are more susceptible to infection of SARS-CoV-2.

Clinical manifestations of individuals infected with SARS-CoV-2 range from asymptomatic to critical illness and even death. Common symptoms of COVID-19 include fever, cough, fatigue, dyspnea, loss of smell and taste, gastrointestinal symptoms such as nausea, diarrhea, anorexia, abdominal pain, belching and emesis. Typical chest CT patterns in patients with pneumonia will show unilateral or bilateral subpleural ground-glass opacity, consolidation with lower lobe prominence. Characteristic laboratory changes include leukocytosis, lymphopenia, eosinopenia, elevated serum levels of procalcitonin, C-reactive protein, lactate dehydratases, D-dimer, et al9. Severe and critically ill patients may develop acute respiratory distress syndrome (ARDS) and require oxygen supplement and even mechanical ventilation.

Children infected with SAR-CoV-2 usually present with mild illness, brief disease course and rare requiring hospital admission; therefore, children are at a lower risk of severe COVID-19 outcomes10. However, a cluster of COVID-19 children with hyperinflammatory shock with features similar to Kawasaki disease and toxic shock syndrome were reported in England and USA. The manifestations of reported multisystem inflammatory syndrome in these children (MIS-C) with positive SARS-CoV-2 test results include shock, cardiac dysfunction, abdominal pain, and markedly elevated inflammatory markers11.  A study of 99 children with MIS-C from New York State, USA, reported an 80% ICU admission rate and 2 death cases12.

In adults, different risk factors associated with severe and critically ill COVID-19 have been identified, as shown in Table 1.

Table 1. Categories of possible risk and protective factors for severe and critically ill COVID-19 according to the strength of current available evidence.

Abbreviations: AKI: Acute kidney injury; ALT: alanine aminotransferase; AST: Aspartate aminotransferase; BUN: Blood urea nitrogen; CKD: Chronic kidney disease; CLD: Chronic liver disease; COPD: Chronic obstructive pulmonary disease; CRP: C-reactive protein; CT: Computed tomography; cTNI: Cardiac troponin I; HIV: human immunodeficiency virus; IEI: inborn error of immunity; IFN: Interferon; IL-1b: Interleukin-1b; IL-6: interleukin-6; ILD: Interstitial lung disease; KL-6: Krebs von Lungen-6; LDH: Lactate dehydrogenase; PCT: Procalcitonin. (Gao Y-d, Ding M, Dong X, et al. Risk factors for severe and critically ill COVID-19 patients: a review. Allergy 2020; doi:10.1111/all.14657.)


Cytokine storm and COVID-19

In severe and fatal cases of COVID-19, it has been found that pro-inflammatory cytokines are excessively produced and released, known as “cytokine storm”13. The innate and adaptive immune systems recognize the invading viruses and react against the infection, accompanied by various cytokines releasing. However, the cytokine storm can be induced by exaggerated responses of the host’s immune system and large numbers of pro-inflammatory cytokines released by activated cells including macrophages, dendritic cells, natural killer cells, neutrophils, monocytes, B cells, T cells and resident tissue cells, such as epithelial and endothelial cells14. The cytokines are involved in an aggressive inflammatory immune response, interact with complements and coagulation system, and subsequently induce tissue damage, systemic inflammation, disseminated intravascular coagulation (DIC) and multiorgan dysfunction syndrome (MODS), thus leading to poor clinical prognosis15. In SARS-CoV-2 infection, lung injury can result from the cytokine storm and progress into hypoxemia and ARDS, which are the characteristics of severe COVID-1916.

Interferon (IFN)-γ, interleukin (IL)-1β, IL-6, IL-12, IL-17 and tumor necrosis factor (TNF)-α are also important in the cytokine storm17; among them, IL-6 might be the most important cytokine involved in cytokine storm.  Higher IL-6 levels were found in non-survivors than survivors18,in severe cases than that in mild cases19, and in those requiring mechanical ventilation20. Another study reported increased levels of IL-10, IL-6 and TNF-α in severe cases compared to moderate cases21. On the other hand, a clinical trial showed that tocilizumab, an IL-6 receptor antagonist, immediately improved the symptoms, hypoxemia, and CT opacity changes in severe and critical COVID-19 patients22.

The cytokine storm is likely to be one of the common contributors to severity and mortality of COVID-19. However, the exact mechanisms of cytokine storm and its network in COVID-19 remain to be further studied and elucidated. Meanwhile, therapies targeted at the pro-inflammatory cytokines under clinical trials might be promising approaches to improve the prognosis of severe patients.


Type I interferons and COVID-19

Interferons (IFNs) usually form part of the body's natural innate immune defenses against viruses. They are secreted by various cell types, notably plasmacytoid dendritic cells, upon recognition of viral components by pattern recognition receptors (PRR)23. Type I IFNs bind to IFN-α receptors (IFNAR)1/2 to activate the JAK–STAT signaling pathway, followed by phosphorylation of STAT1 and STAT2 via cytoplasmic protein JAK1 and TYK2 kinases. STAT1 and STAT2 heterodimers translocate into the nucleus and are recruited for transcription of the IFN-stimulated gene24. SARS-CoV nsp1 inhibits phosphorylation of STAT1, and accessory proteins ORF6 inhibits translocation of STAT1 to the nucleus25. Type I, II, and III IFNs all induced canonical ISGs, with type I IFN (INF-I) being a more potent or rapid inducer than type III IFN and type II IFN inducing the lowest levels of ISGs26.

Human coronavirus inhibits (IFN-I) production. The innate immune system recognizes coronaviruses by various pathogen recognition receptors, TLRs and RLRs, transcription factors nuclear factor-kB (NF-kB) and interferon regulatory factor 3 and 7 (IRF3, IRF7) and stimulate the production of IFN-I. The binding of activated IRF-3 to the interferon promoter is necessary for interferon induction27. The structural (M) and accessory (ORF 4a, ORF 4b, ORF 5) proteins of MERS-CoV inhibit the function of IRF-3 and ORF 4a inhibits the function of NF-κB28. Nucleocapsid (N) protein and nsp3 also interferes with IRF3 function and block phosphorylation and nuclear translocation of IRF3. These mechanisms may contribute to the low IFN-I in duction in cells infected with SARS-CoV-229,30.

Serum levels of IFN-I levels in of SARS-Cov-2 infected patients are below the detection limitation of commonly used assays, yet ISG expression is detected4,31. Study suggested that low levels of IFN-I is one of the driving features of COVID-19, both in cellular and animal models of SARS-CoV-2 infection, in addition to transcriptional and serum profiling of COVID-19 patients32. In mouse model, IFN-I was not detectable in the lung until several hours after the peak in viral load33. Delayed IFN-I response was found in older adults with high viral exposure30. Early IFNs is important in restricting viral replication. The host may benefit from IFN-I supplementation early in the disease course, particularly when IFN-I expression is delayed or reduced due to viral suppression of IFN response or older age of the host28,30 (Figure 1).


Figure 1: Type 1 IFNs Immunity in COVID-19

Legend: Type 1 interferon (IFN-I) immunity in patients with life-threatening COVID-19.  IFN-I is vital in the immunity against virus infection and a robust IFN-I response was suggested to contribute to severe disease due to hyperinflammation. In young people with low viral exposure, early robust IFN-I response results in rapid viral clearance and mild disease; in older adults with high viral exposure, delayed IFN-I response will lead to viral persistence, inflammation and severe disease; in patients with genetic mutations in IFN-I pathways or neutralizing auto-Abs to type I IFNs, there is only low or no IFN-I response, which results in no viral clearance, persistent inflammation and severe disease; in those patients receiving early treatment with injected or inhaled recombinant type I IFNs, rapid viral clearance will result in mild disease. (Gao YD,  et al. Risk factors for severe and critically ill COVID-19 patients: A review. Allergy. 2020 Nov 13. doi: 10.1111/all.14657. Epub ahead of print.)

At least 10% of patients with life-threatening COVID-19 pneumonia have neutralizing auto-Abs against IFN-I34. These auto-Abs prevents IFN-I from binding to the receptors. They were not present in mild symptomatic and asymptomatic COVID-19 patients and only in 4/1277 of healthy controls30. Screening of auto-Abs in SARS-CoV-2-infected patients  may be helpful to identify those at risk of developing life-threatening pneumonia30,34 (Figure 2).


Figure 2. Neutralizing autoantibodies against type I IFNs.


Legend: In 101 of 987 (10.2%) life-threatening COVID-19 patients, neutralizing IgG autoantibodies (auto-Abs) against IFN-ω (in 13 patients), the 13 types of IFN-α (in 36 patients), or both (in 52 patients), were found at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. By contrast, these auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. These auto-Abs neutralized the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. The underlying mechanisms of these neutralizing auto-Abs impairing type I IFN immunity are depicted in this figure. ISGs: interferon-stimulated genes; IFNAR: IFN-α receptors. (Bastard P et al., Science 2020 Sep 24) (Gao YD,  et al. Risk factors for severe and critically ill COVID-19 patients: A review. Allergy. 2020 Nov 13. doi: 10.1111/all.14657. Epub ahead of print.)

Recent studies highlight the potential for IFNs to enhance expression of host ACE24,35. All the IFNs were able to limit the replication of SARS-CoV-2, suggesting that their antiviral actions can partly counterbalance the effect of increased ACE2. All three types of IFNs can strongly inhibit SARS-CoV-2 replication by inducing Zinc finger antiviral protein (ZAP) expression36. ZAP is preferentially targeting CpG dinucleotides in viral RNA sequences, restricts SARS-CoV-2.

In vitro studies suggest that SARS-CoV-2 is substantially more sensitive to IFN-I than other coronaviruses. Treatment of cultured airway epithelial cells with IFN-I was able to inhibit SARS-CoV-2 infection37.  IFN-I introduction at the early stage of SARS-CoV-2 infection might be key to the effectiveness of the IFN-I treatment38Early treatment with recombinant IFN-I resulted in a dampening of cytokine and chemokine release that lowered the migration of neutrophils and other cells in lung39. The trial guidelines in China for the treatment of COVID-19 include inhalation of IFN-α. This route of delivery has the benefit of targeting IFN-α to the respiratory tract25. Human stem cell-based alveolospheres pretreated with low-dose IFNs show a reduction in viral replication, suggesting the prophylactic effectiveness of IFNs against SARS-CoV-240.


Allergy and COVID-19

Allergy or atopic status is defined as genetic predisposition to induce Type 2 immune response following exposure to environmental antigens41. Allergy was supposed to play protective role during COVID-19 42-45. Allergic subjects with eosinophilia were less affected by COVID-19. In contrast, eosinopenia was reported frequently in deceased patients in COVID-1946, and was considered as predictor of disease outcome10. In an Italian study, eosinophil count was higher in COVID-19 children with allergy 47. During respiratory virus infection, eosinophils are involved in immune response conducting cytokine release and recruitment of CD8+ T cells. In addition, eosinophil-derived enzymes can also neutralize virus. Reduced eosinophil count was related to CD8+ T cell depletion, eosinopenia presented overconsumption of eosinophil due to higher viral load47,48.

Transcriptome study showed reduced ACE2 expression in differentiated airway epithelial cell treated with IL-13. Moreover, its expression was inversely related to allergic sensitization in nasal epithelium, and type 2 biomarkers (e.g. IgE level, FeNO and nasal epithelial IL13 expression). Reduced ACE2 expression was also found after cat allergen exposure. In asthma, ACE2 expression was phenotype-dependent, atopic asthma subjects had lowest ACE2 expression, whereas non-atopic asthma subjects had normal ACE2 expression43.

The relation between ACE2 expression and allergy was also reported in other studies with consistent finding 44,45. In ex vivo airway epithelial cells, type 2 asthma and allergic rhinitis showed higher TMPRSS2 expression. Additionally, its expression was positively correlated with type 2 cytokines45. Treatment of allergic disease could also interfere with the viral infection since lower expression of ACE2 and TMPRSS2 obtained following administration of inhaled corticosteroids (ICS)49.

There was cell type specific expression of ACE2 and TMPRSS2 in the nasal airway. ACE2 was expressed with highest frequency among basal/early secretory cells, ciliated cells, and secretory cells. Moreover, it was involved in interferon response network induced by viral infection. In addition, T2 and viral infection driven regulation was also confirmed at ACE2 protein level. Compared to ACE2, TMPRSS2 had a higher frequency among the different cell types, and was determined as mucus secretory gene induced by T2 inflammation50.

There might be other mechanism in terms of allergy and respiratory virus infection. e.g. IgE against RSV was reported involved in antiviral response in human, and with higher level in asthmatic subjects51. Although the maladaptive immune response induced would possibly lead to wide airway viral infection, future studies concerning SARS-CoV-2 infection in airway are still needed to confirm this hypothesis52.

Severe and untreated atopic dermatitis (AD) are susceptible for disseminated viral skin infection53. Since skin manifestations were reported in COVID-19, Radzikowska and Ding et al. dissected the expression of SARS-CoV-2 receptors and their associated molecules in AD based on RNA sequencing. Compared to healthy control, higher expression of TMPRSS2 and PPIASLC7A5, and other associated molecules could be found in non-lesional skin or lesional skin of AD patients. Interestingly, compared to non-lesional skin, lesional skin showed increased expression of cyclophilins, CD98, GLUT1, integrins, etc 54. Although skin is not considered to be sites of viral entry, further studies are needed to explore the relationship between skin allergy and COVID-19.



In summary, SARS-CoV-2 infection is sweeping the globe. COVID-19 is clinically heterogeneous with different disease course and outcomes. Cytokine storm is the main driving factor for severe and critically ill COVID-19. IFN-I is critical to the antiviral immunity against SAR-CoV-2 infection and its insufficiency may contribute also to the severe outcome of this disease.  The relationship between allergy and SARS-CoV-2 is still not fully understood and need to be investigated further.



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