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 Table of Contents  
Year : 2022  |  Volume : 13  |  Issue : 1  |  Page : 45

Immune responses in SARS-CoV-2, SARS-CoV, and MERS-CoV infections: A comparative review

Dental Research Centre, Oral Pathology Department, Dental Faculty, Hamadan University of Medical Sciences, Hamadan, Iran; Pathology Department of Faculty of Medicine, Griffith University, Gold Coast, Australia

Date of Submission27-Jul-2020
Date of Acceptance21-Sep-2021
Date of Web Publication12-Mar-2022

Correspondence Address:
Soussan Irani
Dental Research Centre, Oral Pathology Department, Dental Faculty, Hamadan University of Medical Sciences, Postal code: 65178-38741, Hamadan

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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijpvm.IJPVM_429_20

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Coronavirus, discovered in the 1960s, is able to infect human hosts and causes mild to serious respiratory problems. In the last two decades, the severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been recognized. It has long been demonstrated that MERS-CoV binds to dipeptidyl peptidase 4 and SARS-CoV binds to angiotensin-converting enzyme 2. A “cytokine storm” is the main pathophysiology of aforementioned viruses. Infiltration of neutrophils at the site of the infection is a risk factor for the development of acute respiratory distress syndrome and death. The new coronavirus, SARS-CoV-2, has infected more people than SARS-Cov and MERS-CoV as it can easily be transmitted from person to person. Epidemiological studies indicate that majority of individuals are asymptomatic; therefore, an effective and an efficient tool is required for rapid testing. Identification of various cytokine and inflammatory factor expression levels can help in outcome prediction. In this study we reviewed immune responses in SARS-CoV, Mers-CoV, and SARS-COV-2 infections and the role of inflammatory cells.

Keywords: Adaptive immunity, coronavirus; cytokine storm, SARS-CoV-2

How to cite this article:
Irani S. Immune responses in SARS-CoV-2, SARS-CoV, and MERS-CoV infections: A comparative review. Int J Prev Med 2022;13:45

How to cite this URL:
Irani S. Immune responses in SARS-CoV-2, SARS-CoV, and MERS-CoV infections: A comparative review. Int J Prev Med [serial online] 2022 [cited 2023 Jan 27];13:45. Available from: https://www.ijpvmjournal.net/text.asp?2022/13/1/45/339527

  Introduction Top

Coronavirus, discovered in the 1960s, is a RNA virus. Six species have been known to infect human hosts. They cause mild to serious respiratory problems. In the last two decades, severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) have been recognized. These zoonotic and pathogenic coronaviruses have caused global or regional outbreaks. Recently, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been identified. It causes COVID-19, a respiratory illness. In a very short time, COVID-19 became the greatest health challenge worldwide.[1]

COVID-19 disease has some similarities with other viral diseases such as SARS and MERS. For example, all are initiated by zoonotic transmission and spread rapidly among humans. In addition, they cause severe respiratory illness and death, and all can develop a cytokine storm.[2],[3] However, when they enter host cells, MERS-CoV binds to dipeptidyl peptidase 4 and SARS-CoV and SARS CoV-2 bind to angiotensin-converting enzyme 2 (ACE2).[4] SARS-CoV-2 has more affinity for ACE2 receptors makes it spread so easily.[5] Additionally, SARS-CoV-2 infects and replicates within endothelial cells. SARS-CoV-2 can infect both alveolar epithelium and pulmonary microvascular endothelium.[6] During SARS-coV-2 infection, a part of pathogenesis is caused by thrombin activation which results in thrombotic complications.[7]

The immune responses have essential roles in the resolution of a viral infection, but they can also result in immune pathogenesis. If the immune system functions properly and in the absence of any basic disease, the virus can be effectively suppressed in the acute phase. Nonetheless, when the body fails to produce an adequate adaptive response, a cytokine storm and diffuse organ involvement occur.[4] Increasing evidence shows that the development of an adaptive immunity is controlled by the invading microorganisms and innate immune systems.[8] The aim of this review was to gain improved understanding of the mechanisms of immune responses against coronaviruses, which are essential in the development of a safe prophylactic vaccine. Besides, studying the immune responses in SARS patients and MERS patients can improve the treatment strategies of SARS-Cov-2-infected patients.[9],[10]

  The Possible Transmission Routes Top

Although the mentioned viruses have a zoonotic nature, they rapidly spread from human to human. The transmission route of SARS-CoV-2 is controversial. It is suggested that virus is transmitted from person to person through droplets.[11] Saliva has a great impact on the transmission of infection. Coronaviruses, including SARS-Cov-2, have been demonstrated in saliva. SARS-Cov-2 virus has been detected in both salivary gland ducts and gingival crevicular fluid (GCF).[12] Besides, ocular surface is a potential infection route for both the entry and exit of the virus.[13] Of note, SARS-Cov-2 can be found in sputum, stools, urine, blood/serum, tear, and cerumen samples.[14],[15] SARS-CoV binds to the host cells through its target receptor, the ACE2 protein. It is also believed that SARS-CoV might pass via the mucous membranes, particularly nasal and larynx mucosa then enters the lungs.[16] DPP4, the receptor for MERS-CoV, is expressed in type I and type II alveolar cells, bronchial epithelium, endothelial cells, alveolar macrophages, and leukocytes. Like the virus of SARS, MERS-CoV can infect and replicate in the human airway epithelial cells.[17]

  Hypothetical Pathogenesis of SARS-CoV-2, SARS-CoV, and MERS-CoV Top

SARS-CoV-2 enters alveolar cells expressing ACE2 and transmembrane protease serine 2. Replication of the virus results in releasing viral nucleic acids which are recognized by other cells including epithelial cells, endothelial cells, and alveolar macrophages. Consequently, proinflammatory cytokines and chemokines including IL-6, IP-10, macrophage inflammatory protein 1 alpha (MIP-1α), MIP1β, and monocyte chemoattractant protein-1 (MCP-1/CCL2) are generated. Then, T cells, monocytes, and macrophages infiltrate to the site of infection which enhance more inflammation. Accumulation of immune cells in the lungs causes a “cytokine storm” which circulates in other organs.[18] A cytokine storm in response to type 1 and type 2 T helper (Th) cells has been proposed as the main pathophysiology of COVID-19 infection.[19] It has also been suggested that proinflammatory cytokine/chemokine responses result in apoptosis of lung epithelial cells and endothelial cells.[20]

ACE2 is also expressed on oral epithelial cells. Higher expression of ACE2 has been indicated in the tongue mucosa suggesting the susceptibility of oral cavity to SARS-CoV-2 infection. ACE2 also distributes in the salivary gland tissues. ACE2 receptors can be detected on salivary duct epithelial cells, early targets of SARS-CoV-2 infection. It is suggested that SARS-Cov-2 fuses into the salivary duct epithelial cells, replicates in them, and be released into saliva.[21] Vimentin, an intermediate filament protein, has a great impact on different cellular processes such as cell division and migration.[22],[23] Besides, vimentin contributes to pathological conditions such as immune responses and autoimmune diseases. Vimentin is a cytoplasmic protein; however, it can be found at extracellular locations or at the surface of different cell types.[24] Interestingly, at the cell surface, it functions as a receptor for bacterial and viral pathogens. Regarding SARS-CoV, vimentin has a key role in virus attachment and entry. As vimentin is produced by activated macrophages, it can act as a proinflammatory factor. It can also induce the proinflammatory cytokines and tissue damage. On the other hand, vimentin presents in M2 macrophages; hence, it may accelerate lung repair.[25] A recently published study has shown the potential interactions between vimentin and several SARS-CoV-2 proteins including S protein. The authors have suggested that extracellular vimentin might act as an important component of the SARS-CoV-2 spike protein-ACE2 complex, which mediates SARS-CoV-2 cell entry. Therefore, vimentin may increase SARS-CoV-2 host cell invasion by functioning as an attachment factor.[26] Accumulating evidence suggests that SARS-CoV-2 infection promotes the innate and adaptive immune cell activation in infected host. An impaired immune system combined with a basic disease cannot effectively control the virus in the acute phase; hence, the patient enters a critical and severe phase.[27] Some of SARS proteins such as replicase, spike, Orf3, Orf4, Orf13, envelope, membrane, and nucleocapsid can stimulate T cell responses, which are correlated with higher neutralizing antibody activity.[28] The pathophysiology of SARS- CoV-2 infection depends on aggressive inflammatory responses causing damage to the airways. Thus, disease severity depends on both the viral infection and the host response.[29],[30] Higher number of neutrophils and monocytes in the lung tissue and peripheral blood, serum cytokines, and chemokine levels are higher in severe cases compared to those in mild to moderate cases.[20] SARS-CoV virus can avoid innate antiviral type I interferon (IFN) responses of host cells in order to prolong viral replication and survival.[8] MERS-CoV is also able to manipulate the innate and acquired immune responses, block, or prevent IFN production pathways.[31]

  Clinical Features Top

According to the clinical investigations, the mean incubation period of SARS-CoV-2 is 7.8 days. However, the clinicians recommend a quarantine period of 14 days.[32] The incubation periods of MERS-CoV and SARS-CoV are about 4.5–5.2 days and 4.0 days, respectively.[33] The clinical features vary from asymptomatic and mild clinical symptoms to acute respiratory-distress syndrome and death.[34] In addition to respiratory tract, coronavirus infections may involve other organs/systems including heart, gastrointestinal tract, liver, kidney, skin, and eyes.[35] SARS-CoV and SARS-CoV-2 have similar clinical features including fever, pneumonia, dyspnea myalgia, dry cough, and fatigue.[36] Due to excessive viral immunoreaction and SARS-CoV-2 entry into salivary glands, chiefly parotid and submandibular glands, salivary tissue damage may happen. Consequently, chronic obstructive sialadenitis may develop which is associated with swelling, pain, and discomfort in affected salivary glands.[21] Advanced age, male gender, cardiovascular disease, and risk factors such as hypertension, diabetes, and obesity are associated with poor prognosis.[37] Fever, dyspnea, cough, generalized fatigue, vomiting or diarrhea, abdominal pain, confusion, and myalgia or arthralgia are common in patients with MERS-CoV infection.[38]

  Immune Responses in MERS-CoV, SARS-CoV, and SARS-Cov-2 Top

Due to the cytokine storm, different types of coronaviruses can cause severe pathogenic responses resulting in severe pneumonia, pulmonary edema, multiple organ failure, and even death. Both MERS-CoV and SARS-CoV are able to infect monocytes, macrophages, dendritic cells (DCs), and activated T cells,[39] however, only MERS-CoV can replicate in the infected macrophages and DCs to induce inflammatory responses and impaired apoptosis in T cells. These findings may explain higher mortality rate of MERS-CoV infected patients.[40] Besides, MERS-CoV can infect human airway epithelial cells. MERS-CoV infection results in increased expression of IFN-β, CXCL10 (interferon-γ-inducible protein; IP-10), and MxA.[39],[40] MERS-CoV infection also triggers the production of IFN-α by infected cells, which causes the release of some chemokines including MCP-1, CXCL10, and IL-10 to mediate T cell recruitment.[31] In addition, remarkable upregulation of TNF-α, IFN-ɣ, CCL2, CCL3, CCL5, IL-12, and IL-17 has been indicated.[41],[42] Nevertheless, some studies did not detect TNF-α expression in most patients infected with MERS-CoV.[43],[44] IFNγ has a critical role in early immunity by stimulating both CD8+ and natural killer (NK) cells to induce apoptosis of infected cells.[45] Downregulation of IFNγ and Th1-associated cytokines has been demonstrated in the lower respiratory tract of MERS-CoV-infected patients.[44] Elevated plasma concentrations of IL-6, IL-1RA, IP-10, and MCP-1 are detectable at the acute phase of MERS-CoV infection.[43] IL-6 is produced by T-cells, macrophages, DCs, and B-cells and promotes the proliferation of T-cells.[46] IL-6 is involved in trafficking of leukocytes, especially neutrophils which are important in pathogenesis of inflammatory reactions.[47] IL-6 inhibits the secretion of IFNγ by blocking CD8+ cells.[34] SARS-CoV-2 infection is associated with a proinflammatory phase, which is characterized by elevated levels of cytokines including IL-1β, IL-1Rα, IL-2, IL-6, IL-10, fibroblast growth factor, TNF-α, granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte-colony stimulating factor (G-CSF), IP-10, MCP-1, MIP-1α, platelet-derived growth factor, and vascular endothelial growth factor (VEGF). Among them, the expression of IL-6 has a crucial role across the immune system and is mainly correlated with increased mortality. Increased IL-6 signaling promotes the maturing naïve T cells into effector T cells, induces VEGF expression in epithelial cells, increases vessel permeability, and decreases myocardium contractility.[48] SARS-CoV-2 infects human lung tissues more effectively than SARS-CoV; however, SARS-CoV can trigger higher levels of proinflammatory cytokines and IFNs.[36] Interestingly, elevated IL-6 level in SARS-CoV-2-infected patients is higher than the patients with SARS-CoV or MERS.[49] A previously published paper has indicated that excessive amounts of inflammatory cytokines (IL-6, IL-10, IL-2, and IFN-γ) are correlated with COVID-19 severity.[50] CXCL10 (IP-10) has also been evaluated in viral infections. Neutrophils, endothelial cells, keratinocytes, fibroblasts, DCs, astrocytes, and hepatocytes are able to produce IP-10. CXCL10 binds to chemokine receptor 3 (CXCR3) to recruit T cells, monocytes, and NK cells. Enhanced serum level of IP-10 has been observed in patients with COVID-19 especially in the most severe cases.[45] Additionally, increased expression levels of IP-10, monocyte-chemotactic protein 3 (MCP-3), hepatocyte growth factor, monokine-induced gamma IFN (MIG), and MIP-1α are highly associated with disease severity during disease progression. Among them, IP-10 and MCP-3 are excellent predictors for progression of COVID-19.[51] In addition, upregulation of IP-10 in airway epithelial cells and lung fibroblasts is associated with severity of MERS-CoV infection.[52] Increased serum levels of IL-6 and IP-10 within 2 weeks can be indicated in severe cases with MERS infection.[53] Elevated CXCL10 expression levels have been detected in lung tissues during early stages of SARS-CoV infection; however, some of the inflammatory factors such as CCL3, CCL27, CXCL2, and CXCL8 are increased in lung tissues during late stages of the disease.[54] Elevated expression of proinflammatory cytokines including MCP-1, TGF-β1, TNFα, IL-1β, and IL-6 has been indicated in autopsy tissues from patients who died of SARS-CoV.[55] Besides, enhanced expression levels of IL-1α, IL-1β, and IL-8 can be measured in the lower respiratory tracts of patients infected with MERS-CoV and are associated with tissue damage and acute inflammatory responses, which lead to severe pathogenesis and mortality.[44] IL-8 has a great impact on neutrophil recruitment and activation. It is hypothesized that high IL-8 expression levels may cause the formation of neutrophil extracellular traps (NETs), web-like structures of DNA, and proteins; therefore, this results in severe MERS-CoV infection.[44] In addition, increased expression of IL-8 in MERS-CoV-infected patients may upregulate CD4 molecules to enhance helper T cell infection.[44] Elevated expression levels of IL-7 and IL-15 were also recorded in most patients with MERS infection.[56] IL-7 plays a key role in T-cell homeostasis. Increased serum IL-7 level in severe cases of COVID-19 patients may indicate a homeostatic mechanism.[46] MERS-CoV infection also induces Th17 cytokines which recruit neutrophils and monocytes to the site of infection or inflammation.[42] Th2 cytokines have a great impact on the humoral immune responses. MERS-CoV infection is able to downregulate the Th2 responses.[44] Increased serum level of IL-12 has also been found in SRAS-CoV-2- and SARS-CoV-infected patients.[57]

Antibody response to MERS-CoV can be found in the second and third week after the onset of infection. In patients with pneumonia, antibodies can be detected 13 months after infection.[58] In SARS-CoV infection, IgM and IgG are produced and can be detected in patient's blood 3–6 and 8 days after infection, respectively.[59] Regarding SARS-CoV-2 infection, IgM can be idetected in early-stage infection (peaks after 2 weeks); however, IgG peaks in 3 weeks and maintains at a high level for over 48 days.[60] Higher IgG level can be observed during late stages or postrecovery.[61]

Toll-like receptors (TLRs) signaling pathways control the MERS-CoV infection. TLRs are the key mediators of innate immune response, and the spike protein of MERS-CoV is able to inhibit the TLR signaling pathways.[31] Stimulation of TLRs activates the nuclear factor-κB (NF-κB) signaling pathway, which results in the production of inflammatory factors from monocytes including IL-1, TNF-α, and IL-6 to control virus infections. The innate immune reaction signaling initiates by TLR2 through NF-kB in macrophages, monocytes, and epithelial cells.[62] The binding of SARS-CoV-2 to TLRs results in the release of pro-IL-1β, which is a mediator of lung inflammation, fever, and fibrosis.[63] During infection with SARS-CoV, TLR2 expression allows for IL-8 production in response to S protein.[64] Activation of TLR4 signaling increases cell surface expression of ACE2 to facilitate virus entry. It has also been shown that after entry to host cells, SARS-CoV-2 is recognized chiefly by TLR7 in endosomes.[65] NETs formation by neutrophils in the lungs of patients with SARS-CoV-2 may be induced via TLR7 signaling.[66] Also, activation of TLR7 results in the production of TNF-α, IFN-α, IL-12, and IL-6 to generate specific cytotoxic CD8+ T cells.[67] The Notch pathway has a functional role during the activity of innate and adaptive immune cells. In patients with COVID 19. Notch1 binds to IL-6 promoter in macrophages in response to IFN-γ resulting in IL-6 production. In turn, IL-6 increases the expression of delta-like ligand-1 to amplify the Notch signaling.[68] JAK1 and JAK3 also promote several cytokines function involving in antiviral responses such as IFNγ, IL-2, IL-15, and IL-21. Therefore, it is proposed that JAK1/JAK3 enhances the clearance of SARS- CoV-2. However, JAK2 facilitates SARS- CoV-2 entrance. Besides, JAK2 signaling induces the production of IL-6 and GM-CSF.[69] The transcription factor NFκB induces the transcription of proinflammatory cytokines. Activation of NFκB has been recorded in infections with both SARS-CoV and MERS-CoV. In MERS-CoV-infected patients, Th17 cells are able to produce IL-17 via the STAT3 and NF-κB signaling pathways.[31] Also, increased expression level of IL-10 in MERS-CoV-infected patients has been indicated. IL-10 has an antiinflammatory effect mediated through JAK-STAT pathway.[42]

  The Role of Inflammatory Cells Top

In acute phase of MERS-CoV infection, proinflammatory Th1 and Th17 responses can be found with increased concentrations of IFN-γ, TNF-α, IL-15, and IL-17.[42] Th2 cells stimulate antibody production by secreting IL-4, IL-5, IL-9, IL-10, and IL-13.[70] Overactivation of CD8+ T cells can also be detected in acute phase of MERS-CoV infection, though CD4+ T-cells play a minor role in acute phase.[43] Neutrophils are the most abundant immune cells in the innate immune system. Neutrophils play a critical role in the clearance of pathogens and debris through phagocytosis. It has been suggested that neutrophils promote antiviral defenses via different mechanisms and cytokine release.[62] Neutrophils release NETs for viral inactivation and cytokine production to restrict virus replication. On the other hand, neutrophils are highly immunogenic and toxic to the host tissue and cause inflammation, and epithelial and endothelial cell death. Increased neutrophil and monocyte counts have been observed in more severe and fatal cases of MERS infection.[56],[71] Migration and recruitment of neutrophils have been induced by the proinflammatory cytokines such as IL-8, TNF-α, and IL-6.[72] CD8+ T cells contribute to MERS-CoV clearance by producing IFN-γ and granzyme.[31]

A significant increase of Th-1-related cytokines, interferons, and IL-2, IL-12, IFN-γ, and TNF-α has been indicated in mild cases of SARS-CoV patients.[72] Increased expression level of IL-2 has also been found in SARS-CoV patients. IL-2 is produced by CD4+ T cells and CD8+ T cells.[73] Decreased number of CD4+ and CD8+ T cells has been shown at the early phase of SARS-CoV infection and is associated with adverse outcomes. It is believed that activation of IP-10 results in a significant decrease in peripheral CD4+, CD8+ T lymphocytes, and NK cells.[74] Th-1 cell phenotype stimulates the proliferation and activation of cytotoxic T lymphocytes and promotes the phagocytic activity of macrophages in SARS infections.[72] In addition, a marked elevated of Th2 cytokines (IL-4, IL-5, IL-10) has been reported in fatal SARS cases.[28] A previous in vivo study has shown the production of IP-10, CCL-2, CXCL-1, and CXCL-3 by neutrophils. The authors have suggested that neutrophils may induce other cell types to synthesize these chemokines.[75] DCs and macrophages are attracted to the site of infection via increased expression levels of CXCL-10/IP-10, CCL-2/MCP-1, CXCL-5/RANTES, and CCL-3/MIP-1α. Infected DCs during SARS-CoV infection induce the expression of CCL2, CCL3, CCL5 and CXCL10.[76] In addition, the monocyte differentiation to macrophages is activated by proinflammatory cytokines, including GM-CSF, IFN-α, IL-6, and TNF-α.[77]

SARS-CoV-2 infection is characterized by lower total lymphocyte count (CD4+ and CD8+ T-cells, NK cells, and B cells) in circulation, higher neutrophil and monocyte counts, and an increased production of inflammatory cytokines which are correlated with disease severity and death.[46],[78],[79] Lymphopenia might be caused by increased serum cortisol level.[46] Also, it has been shown that IL-6, produced by infected macrophages, promotes lymphocyte necrosis.[74] Lower T-cell count is because of increased apoptosis and/or reduced proliferation rates.[46] Higher neutrophil-to-lymphocyte ratio, a well-known marker of infection and systemic inflammation, is suggestive for poor prognosis.[79] Besides, a decreased number of circulating CD4+ cells, CD8+ cells, B cells, NK cells, monocytes, eosinophils, and basophils can be indicated.[80] A significant increase in the proportion of naïve helper T cells and reduction in memory helper T cells and regulatory T cells can be detected in SARS CoV-2-infected patients. Rapid reduction of lymphocytes mainly T lymphocytes (both CD4+ and CD8+ T lymphocytes) in peripheral blood has been found in the acute phase of infection.[4] Higher serum levels of IL2, IL7, IL10, GSCF, IP-10, MCP1, CCL3 (MIP1A), and TNF-α in severe cases of COVID-19 patients reflect the activation of T-helper 1 (Th1) cells.[74] It is suggested that the number of CD4+ T and CD8+ T cells is negatively correlated with the levels of TNF-α, IL-6, and IL-10, respectively. This finding may suggest that aforementioned cytokines are involved in a decrease in T cell counts.[81] In patients with COVID-19, overactivation of CD8+ T cells has been documented in COVID-19 cases.[82] However, the ratio of CD4:CD8 remain normal and stable.[83] Overactivation of CD4+ and CD8+ T-cells in the early phase of COVID-19 results in the production of GM-CSF.[74] Nonetheless, CD8+ T cells are cytotoxic killing virus-infected cells via producing the cytotoxic molecules such as perforin and granzyme B.[84] Cell-mediated immunity including T-cells (T helper and cytotoxic) has a great impact on efficient antiviral responses. T cells also have critical roles against viral infections. For instance, CD4+ T cells facilitate virus-specific antibody synthesis via the T-dependent activation of B cells[85] and in SARS-CoV-2 infections; CD4+ T-cells (especially TH1 cells) react to S-protein.[46] Memory CD4+ T cells and CD8+ T cells have been found in 100 and 70% of recovered patients, respectively. It has been suggested that memory T cell reactions are for different SARS-CoV-2 proteins such as spike protein, nucleoprotein, and membrane protein.[86] Additionally, it has been believed that disease severity in COVID-19 may be associated with low IFN-γ production by CD4+ T-cells. The proportion of Th17 cells is augmented in the peripheral blood. Th17 cells are mainly stimulated by IL-6 and IL-23.[50] GM-CSF synthesis is increased during the acute phase of COVID 19 patients by Th17 cells.[45] Additionally, reduced number of NK cells and B cells has been reported in patients with severe COVID-19 patients. A previously published paper has shown that overexpression of inhibitory signals can suppress T-cell and NK cytokine secretion in COVID-19 patients.[87] Reduced functional markers of NK cells (CD107a, IFN-γ, IL-2, and TNF-α) have been consistently reported in COVIC-19 patients compared to healthy controls. Also, a decreased expression levels of granzyme B in the NK cells of the patients have been detected.[78]

Two types of pulmonary macrophages can be indicated: alveolar macrophages, residing close to type I and type II epithelial alveolar cells, and interstitial macrophages which are predominantly found between the endothelial layer and alveolar epithelium zone.[88] Functionally, both macrophages are divided into two types: First, M1 macrophages which are activated by pathogens including viruses. Later, their activation is promoted by Th1 cells. M1 macrophages attract immune cells into the lung parenchyma. Second, M2 macrophages activated by Th2 cells (IL-4, IL-13). Increased activation of M1 macrophages in SARS-Cov-2-infected patients results in the production of inflammatory cytokines. Among the produced cytokines, IP-10 leads to cytokine storm.[89] GM-CSF stimulates monocytes/macrophages to produce IL-6 and some other inflammatory factors.[74] In the upper respiratory tract, macrophages express different chemokines and proinflammatory cytokines such as IL-1B, IL-8, IL-18, and TNF-α.[74] Also, it has been reported that monocytes stimulated NK cells to produce IFN-γ through IL-8.[90]

The production of chemokines and mediators by infected cells results in the infiltration of neutrophils at the site of infection. Neutrophilia may be a risk factor for the development of acute respiratory distress syndrome and death. Neutrophils secrete cytokines and chemokines that attract more immune cells such as T lymphocytes and monocytes. Cytokines such as G-CSF, CXCL10, MCP1, MIP1A, and TNF-α are responsible for attracting neutrophils to the inflammatory sites. These findings may highlight the role of neutrophils in the severity of illness in COVID-19 patients.[91] In COVID-19 patients, the release of NETs can protect the host. In addition, neutrophils produce TNF, IL-6, IL-8, and reactive oxygen species.[62] However, the overproduction of NETs causes lung tissue damage (killing lung epithelial cells) via enzymes such as neutrophil elastase (NE) and myeloperoxidase.[62],[66] Additionally, the increase in platelet-neutrophil aggregates results in increased levels of NET and immunothrombosis formation. Immunothrombosis causes microvascular occlusion in the lung.[92] A previous animal study also found that neutrophilia is associated with hemorrhagic lesions in the lungs of rats with coronavirus infection. Upregulation of ELANE (a NE) in patients with SARS and COVID-19 patients might be the reason for the hemorrhaging of lungs, one of the leading causes of death.[91]

DCs are a diverse group of antigen-presenting cells and play pivotal roles in the initiation and regulation of innate and adaptive immune responses. DCs produce IL-12 and type I IFNs.[93] In addition, DCs produce IL-15 which activate NKcells.[90] [Table 1] summarizes the role of inflammatory cells in SARS-CoV-2, SARS-Cov and MERS-CoV infections.
Table 1: A summary of the role of inflammatory cells in SARS-CoV-2, SARS-Cov, and MERS-CoV infections

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  Diagnosis and Detection Methods Top

[Figure 1] summarizes the pathophysiological mechanism of coronavirus infection resulting in the excessive production of cytokines. Early detection of virus-infected patients has a great impact on the prevention of transmission. The diagnosis of COVID-19 is based on the combination of epidemiologic information such as a history of travel to or residence in affected areas 14 days prior to symptom onset, clinical symptoms, CT findings, and laboratory tests (RT-PCR) on respiratory tract samples.[102] Beside to oropharyngeal swabs specimens, SARS-CoV-2 can be detected in urine, blood, and anal swabs.[103] Analysis of saliva and the GCF is a noninvasive diagnostic method. SARS-CoV-2 can be detected in saliva samples in the early phase of infected patients. In a previous study, saliva was detected in 91.67% of SARS Cov-2 patients a few days after hospitalization.[104] In this study, to confirm that salivary glands were infected with SARS-Cov-2, saliva was directly collected from the opening of salivary glands.[105] Interestingly, very recent study has found that tear sample from a patient with conjunctivitis can also be used as a tool for detection of SARS-CoV-2.[106] Chest CT is a useful diagnostic tool in most patients with COVID-19. In some patients with negative qRT-PCR results but with clinical symptoms, typical CT features are visible. A meta-analysis found that the sensitivity and specificity of initial chest CT scan for highly suspicious individuals for COVID-19 are 87 and 43%, respectively. It means that a chest CT scan can be considered as an adjuvant diagnostic tool.[107] A recently published work has indicated that SARS-CoV-2 antigen and RNA can be detected in formalin fixed paraffin-embedded specimens using immunohistochemistry.[108] Detection with genomic sequencing is also a rapid and complete diagnostic method. This technique is able to investigate SARS-CoV-2 evolution during transmission. Also, this technique can identify several pathogens in a single patient.[109] SARS-CoV antibodies include spike and nucleocapsid proteins. Detection of IgM and IgG against SARS-CoV-2 is a fast and simple screening method.[110] A very recent study has indicated that the combination of IgM and IgG antibodies is an accurate diagnostic test with 84.5% sensitivity and 91.6% specificity.[111] Polymerase chain reaction (PCR) test was rapidly developed for diagnosis of the virus.[112] RT-PCR is the most reliable method for COVID-19 diagnosis. A previously published study on the accuracy of RT-PCR results has indicated that specimens from bronchoalveolar lavage fluid are positive in 93 and 72% of cases, respectively.[113] It seems that pharyngeal swabs have lowest sensitivity and nasal swabs is more sensitive than pharyngeal swabs.[114] Besides, RT-PCR is the gold standard for sputum samples.[111] However, the exact sensitivity and specificity of RT-PCR tests for COVID-19 are not clear, but it is suggested that a positive test is highly suggestive of true infection, but a negative test does not rule out the disease.[114]
Figure 1: Corona virus binds to Lung Epithelial Cells which causes the activation of inflammatory cells and cytokine storms

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In the first 5 days of SARS-CoV infection, throat swabs, nasopharyngeal aspirates, and sputum samples are the most useful clinical specimens, but later viral RNA could be found more readily in stool specimens.[115] Respiratory tissue samples are used to identify patients with MERS-CoV.[116] RT-PCR is also a suitable test for detection of MERS-Cov.[117]

  Therapeutic Strategies For Top

There is still no effective treatment for MERS-CoV or any other coronavirus infections. Supportive care strategies and preservation of renal, hepatic, and neurological function may help clinicians to deal with the infection.[118] To avoid the innate immune responses, SARS-CoV and MERS-CoV use several strategies. Therefore, suppression of IL-1 family members and IL-6 can be considered as a therapeutic strategy in many inflammatory diseases, including viral infections. Besides, IL-37 and IL-38 are able to suppress IL-1β and are considered as potential therapeutic cytokines.[63] Remdesivir was first developed for the treatment of Ebola virus infection. A recent published study has reported that a combination of remdisevir and IFN-β has an antiviral function in MERS-CoV patients.[119]

Due to high level of IL-6, blockade of interleukin-6 signaling may become a new method for the treatment of severe patients. Tocilizumab is a blocker of IL-6R which blocks IL-6 signal transduction pathway.[50] In addition, blocking of IL-6 in severe cases of COVID-19 infections results in increasing the absolute lymphocyte blood count and cytotxic functions of NK cells.[78],[120] Due to the elevated expression of IL-1β in most COVID-19 patients with severe symptoms, inhibition of IL-1 has been suggested as a therapeutic strategy.[121] Also, leukotriene B4 that activates neutrophils is able to kill human coronavirus, respiratory syncytial virus, and influenza B virus. Besides, adaptor-associated protein kinase 1 inhibits SARS-CoV-2 viral infection through clathrin-mediated endocytosis. Endocytosis is a way that viruses enter human host cells.[122] Currently, remdisevir is suggested as an antiviral drug for SARS-CoV-2. Nevertheless, further clinical trials are needed to assess the efficacy and safety of remdesivir for SARS-CoV-2 pneumonia patients.[123] Antiinflammatory drugs including corticosteroids can reduce the effect of cytokine storms and lung damage. A short course of systemic corticosteroids can be tolerated among patients with SARS-CoV-2.[3] The use of glucorticosteroids has been considered as a therapeutic strategy, even so, the timing of administration and the dosage play key roles in the outcome in severe cases. Too early administration of glucocorticoids increases the viral load because it can inhibit the initiation of immune responses. It is suggested that glucocorticoids to be used in severe cases to prevent acute respiratory syndrome.[20] Vaccine seems to elicit both the humoral and cellular immune system. An ideal vaccine is characterized by safety and protection efficacy in large-scale clinical trials. To date, several vaccines have reached to the final stages. Currently, it is not possible to compare different vaccines.[124] Vaccines against SARS-CoV-2 can be divided into three main groups: RNA-, DNA-, and peptide-based vaccines.[125] The phase III clinical studies of mRNA vaccines show efficacy by 95%.[126]

  Conclusions Top

In the past two decades, the world has faced with three coronavirus outbreaks which have caused global health consternation. The new coronavirus, SARS-CoV-2, has infected more people than SARS-Cov and MERS-CoV as it can easily be transmitted from person to person. Epidemiological studies indicate that majority of individuals are asymptomatic. Therefore, an effective and an efficient tool is required for rapid testing. Dysregulation of cytokine levels have been reported in infected patients and immune responses have a great impact on the determination of course of infection. However, cytokine levels differ in severely affected patients and those with moderate or mild symptoms. So, identification of cytokine level can help in recognition of patients with severe disease. Still, further studies are needed to assess the immune differences between different types of coronavirus infections and different patients. Besides, due to high mortality rate, it is crucial to develop antiviral therapeutics and vaccine. To achieve this goal, it is needed to understand the molecular mechanisms of the virus life cycle. A comparative study of SARS-CoV-2 outbreak with the previous coronavirus outbreaks may provide additional light into the most effective therapeutic strategies. As COVID-19 is a serious threat to public health, identifying biomarkers for disease is an urgent need. To identify biomarkers, it is necessary to recognize the involved cytokines and factors.


The author would like to thank the Vice Chancellor of Research of Hamadan University of Medical Sciences and Dental Research Center for supporting this study.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Yan Y, Shin WI, Pang YX, Meng Y, Lai J, You C, et al. The first 75 Days of novel coronavirus (SARS-CoV-2) outbreak: Recent advances, prevention, and treatment. Int J Environ Res Public Health 2020;17:2323.  Back to cited text no. 1
Lipworth B, Chan R, Lipworth S, RuiWen Kuo C. Weathering the Cytokine storm in susceptible patients with severe SARS-CoV-2 infection. J Allergy Clin Immunol Pract 2020;8:1798-801.  Back to cited text no. 2
Runfeng L, Yunlong H, Jicheng H, Weiqi P, Qinhai M, Yongxia S, et al. Lianhuaqingwen exerts anti-viral and anti-inflammatory activity against novel coronavirus (SARS-CoV-2). Pharmacol Res 2020;156:104761. doi: 10.1016/j.phrs. 2020.104761.  Back to cited text no. 3
Lin L, Lu L, Cao W, Li T. Hypothesis for potential pathogenesis of SARS-CoV-2 infection–a review of immune changes in patients with viral pneumonia. Emerg Microbes Infect 2020;9:727-32.  Back to cited text no. 4
Araf Y, Faruqui NA, Anwar S, Hosen MJ. SARS-CoV-2: A new dimension to our understanding of coronaviruses. Int Microbiol 2020;24:19-24.  Back to cited text no. 5
Wang P, Luo R, Zhang M, Wang Y, Song T, Tao T, et al. A cross-talk between epithelium and endothelium mediates human alveolar–capillary injury during SARS-CoV-2 infection. Cell Death Dis 2020;11:1042.  Back to cited text no. 6
Rossi GA, Sacco O, Mancino E, Cristiani L, Midulla F. Differences and similarities between SARS-CoV and SARS-CoV-2: Spike receptor-binding domain recognition and host cell infection with support of cellular serine proteases. Infection 2020;48:665-9.  Back to cited text no. 7
Frieman M, Baric R. Mechanisms of severe acute respiratory syndrome pathogenesis and innate immunomodulation. Microbiol Mol Biol Rev 2008;72:672-85.  Back to cited text no. 8
Roberts A, Lamirande EW, Vogel L, Jackson JP, Paddock CD, Guarner J, et al. Animal models and vaccines for SARS-CoV infection. Virus Res 2008;133:20-32.  Back to cited text no. 9
Abdolahi N, Kaheh E, Golsha R, Khodabakhshi B, Norouzi A, Khandashpoor M, et al. Letter to the editor: Efficacy of different methods of combination regimen administrations including dexamethasone, intravenous immunoglobulin, and interferon-beta to treat critically ill COVID-19 patients: A structured summary of a study protocol for a randomized controlled trial. Trials 2020;21:549.  Back to cited text no. 10
Birgand G, Peiffer-Smadja N, Fournier S, Kerneis S, Lescure F-X, Lucet J-C. Assessment of air contamination by SARS-CoV-2 in hospital settings. JAMA Netw Open 2020;3:e2033232-e.  Back to cited text no. 11
Vinayachandran D, Balasubramanian S. Salivary diagnostics in COVID-19: Future research implications. J Dent Sci 2020;15:364-6.  Back to cited text no. 12
Bernabei F, Versura P, Rossini G, Re MC. There is a role in detection of SARS-CoV-2 in conjunctiva and tears: A comprehensive review. New Microbiol 2020;43:149-55.  Back to cited text no. 13
Zhu Z, Lian X, Su X, Wu W, Marraro GA, Zeng Y. From SARS and MERS to COVID-19: A brief summary and comparison of severe acute respiratory infections caused by three highly pathogenic human coronaviruses. Respir Res 2020;21:1-14.  Back to cited text no. 14
Hanege FM, Kocoglu E, Kalcioglu MT, Celik S, Cag Y, Esen F, et al. SARS-CoV-2 presence in the saliva, tears, and cerumen of COVID-19 patients. Laryngoscope 2021;131:E1677-82.  Back to cited text no. 15
Ni W, Yang X, Yang D, Bao J, Li R, Xiao Y, et al. Role of angiotensin-converting enzyme 2 (ACE2) in COVID-19. Crit Care 2020;24:422.  Back to cited text no. 16
Choudhry H, Bakhrebah MA, Abdulaal WH, Zamzami MA, Baothman OA, Hassan MA, et al. Middle East respiratory syndrome: Pathogenesis and therapeutic developments. Future Virol 2019;14:237-46.  Back to cited text no. 17
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.  Back to cited text no. 18
Perricone C, Triggianese P, Bartoloni E, Cafaro G, Bonifacio AF, Bursi R, et al. The anti-viral facet of anti-rheumatic drugs: Lessons from COVID-19. J Autoimmun 2020;111:102468.  Back to cited text no. 19
Ye Q, Wang B, Mao J. The pathogenesis and treatment of the 'Cytokine Storm' in COVID-19. J Infect 2020;80:607-13.  Back to cited text no. 20
Wang C, Wu H, Ding X, Ji H, Jiao P, Song H, et al. Does infection of 2019 novel coronavirus cause acute and/or chronic sialadenitis? Med Hypotheses 2020;140:109789.  Back to cited text no. 21
Irani S, Jafari B. Expression of vimentin and CD44 in mucoepidermoid carcinoma: A role in tumor growth. Indian J Dent Res 2018;29:333-40.  Back to cited text no. 22
[PUBMED]  [Full text]  
Irani S, Dehghan A. Expression of vascular endothelial-cadherin in mucoepidermoid carcinoma: Role in cancer development. J Int Soc Prev Community Dent 2017;7:301-7.  Back to cited text no. 23
Irani S, Dehghan A. The expression and functional significance of vascular endothelial-cadherin, CD44, and vimentin in oral squamous cell carcinoma. J Int Soc Prev Community Dent 2018;8:110-7.  Back to cited text no. 24
Ramos I, Stamatakis K, Oeste CL, Pérez-Sala D. Vimentin as a multifaceted player and potential therapeutic target in viral infections. Int J Mol Sci 2020;21:4675.  Back to cited text no. 25
Suprewicz Ł, Swoger M, Gupta S, Piktel E, Byfield FJ, Iwamoto DV, et al. Vimentin binds to SARS-CoV-2 spike protein and antibodies targeting extracellular vimentin block in vitro uptake of SARS-CoV-2 virus-like particles. bioRxiv 2021. Pre-print. doi: 10.1101/2021.01.08.425793.  Back to cited text no. 26
Felsenstein S, Herbert JA, McNamara PS, Hedrich CM. COVID-19: Immunology and treatment options. Clin Immunol (Orlando, Fla) 2020;215:108448. doi: 10.1016/j.clim. 2020.108448.  Back to cited text no. 27
Li CK, Wu H, Yan H, Ma S, Wang L, Zhang M, et al. T cell responses to whole SARS coronavirus in humans. J Immunol (Baltimore, Md: 1950) 2008;181:5490-500.  Back to cited text no. 28
Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020;181:271-80.e8.  Back to cited text no. 29
Magrone T, Magrone M, Jirillo E. Focus on receptors for coronaviruses with special reference to angiotensin-converting enzyme 2 as a potential drug target - A perspective. Endocr Metab Immune Disord Drug Targets 2020;20:807-11.  Back to cited text no. 30
Mubarak A, Alturaiki W, Hemida MG. Middle east respiratory syndrome coronavirus (MERS-CoV): Infection, immunological response, and vaccine development. J Immunol Res 2019;2019:6491738. doi: 10.1155/2019/6491738.  Back to cited text no. 31
Lauer SA, Grantz KH, Bi Q, Jones FK, Zheng Q, Meredith HR, et al. The incubation period of coronavirus disease 2019 (COVID-19) from publicly reported confirmed cases: Estimation and application. Ann Intern Med 2020;172:577-82.  Back to cited text no. 32
Jiang X, Rayner S, Luo MH. Does SARS-CoV-2 has a longer incubation period than SARS and MERS? J Med Virol 2020;92:476-8.  Back to cited text no. 33
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.  Back to cited text no. 34
Lai CC, Ko WC, Lee PI, Jean SS, Hsueh PR. Extra-respiratory manifestations of COVID-19. Int J Antimicrob Agents 2020;56:106024. doi: 10.1016/j.ijantimicag. 2020.106024.  Back to cited text no. 35
Chu H, Chan JFW, Yuen TTT, Shuai H, Yuan S, Wang Y, et al. Comparative tropism, replication kinetics, and cell damage profiling of SARS-CoV-2 and SARS-CoV with implications for clinical manifestations, transmissibility, and laboratory studies of COVID-19: An observational study. Lancet Microbe 2020;1:e14-23.  Back to cited text no. 36
Ryan PM, Caplice NM. Is adipose tissue a reservoir for viral spread, immune activation and cytokine amplification in COVID-19. Obesity 2020;28:1191-4.  Back to cited text no. 37
Saad M, Omrani AS, Baig K, Bahloul A, Elzein F, Matin MA, et al. Clinical aspects and outcomes of 70 patients with Middle East respiratory syndrome coronavirus infection: A single-center experience in Saudi Arabia. Int J Infect Dis 2014;29:301-6.  Back to cited text no. 38
Tynell J, Westenius V, Rönkkö E, Munster VJ, Melén K, Österlund P, et al. Middle East respiratory syndrome coronavirus shows poor replication but significant induction of antiviral responses in human monocyte-derived macrophages and dendritic cells. J Gen Virol 2016;97:344-55.  Back to cited text no. 39
Liang Y, Wang M-L, Chien C-S, Yarmishyn AA, Yang YP, Lai W-Y, et al. Highlight of immune pathogenic response and hematopathologic effect in SARS-CoV, MERS-CoV, and SARS-Cov-2 infection. Front Immunol 2020;11. doi: 10.3389/fimmu. 2020.01022.  Back to cited text no. 40
Zhou J, Chu H, Li C, Wong BH, Cheng ZS, Poon VK, et al. Active replication of Middle East respiratory syndrome coronavirus and aberrant induction of inflammatory cytokines and chemokines in human macrophages: Implications for pathogenesis. J Infect Dise 2014;209:1331-42.  Back to cited text no. 41
Mahallawi WH, Khabour OF, Zhang Q, Makhdoum HM, Suliman BA. MERS-CoV infection in humans is associated with a pro-inflammatory Th1 and Th17 cytokine profile. Cytokine 2018;104:8-13.  Back to cited text no. 42
Shin HS, Kim Y, Kim G, Lee JY, Jeong I, Joh JS, et al. Immune responses to Middle East respiratory syndrome coronavirus during the acute and convalescent phases of human infection. Clin Infect Dis 2019;68:984-92.  Back to cited text no. 43
Alosaimi B, Hamed ME, Naeem A, Alsharef AA, AlQahtani SY, AlDosari KM, et al. MERS-CoV infection is associated with downregulation of genes encoding Th1 and Th2 cytokines/chemokines and elevated inflammatory innate immune response in the lower respiratory tract. Cytokine 2020;126:154895. doi: 10.1016/j.cyto. 2019.154895.  Back to cited text no. 44
Costela-Ruiz VJ, Illescas-Montes R, Puerta-Puerta JM, Ruiz C, Melguizo-Rodríguez L. SARS-CoV-2 infection: The role of cytokines in COVID-19 disease. Cytokine Growth Factor Rev 2020;54:62-75.  Back to cited text no. 45
Kalfaoglu B, Almeida-Santos J, Tye CA, Satou Y, Ono M. T-cell dysregulation in COVID-19. Biochem Biophys Res Commun 2021;538:204-10.  Back to cited text no. 46
Fielding CA, McLoughlin RM, McLeod L, Colmont CS, Najdovska M, Grail D, et al. IL-6 regulates neutrophil trafficking during acute inflammation via STAT3. J Immunol (Baltimore, Md: 1950) 2008;181:2189-95.  Back to cited text no. 47
McGonagle D, Sharif K, O'Regan A, Bridgewood C. The role of cytokines including interleukin-6 in COVID-19 induced pneumonia and macrophage activation syndrome-like disease. Autoimmun Rev 2020;19:102537. doi: 10.1016/j.autrev. 2020.102537.  Back to cited text no. 48
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.  Back to cited text no. 49
Zhang C, Wu Z, Li JW, Zhao H, Wang GQ. Cytokine release syndrome in severe COVID-19: Interleukin-6 receptor antagonist tocilizumab may be the key to reduce mortality. Int J Antimicrobial Agents 2020;55:105954. doi: 10.1016/j.ijantimicag. 2020.105954.  Back to cited text no. 50
Yang Y, Shen C, Li J, Yuan J, Wei J, Huang F, et al. Plasma IP-10 and MCP-3 levels are highly associated with disease severity and predict the progression of COVID-19. J Allergy Clin Immunol 2020;146:119-27.  Back to cited text no. 51
Aboagye JO, Yew CW, Ng OW, Monteil VM, Mirazimi A, Tan YJ. Overexpression of the nucleocapsid protein of Middle East respiratory syndrome coronavirus up-regulates CXCL10. 2018;38. doi: 10.1042/BSR20181059.  Back to cited text no. 52
Kim ES, Choe PG. Clinical progression and cytokine profiles of Middle East respiratory syndrome coronavirus infection. J Korean Med Sci 2016;31:1717-25.  Back to cited text no. 53
Majumdar S, Murphy PM. Chemokine regulation during epidemic coronavirus infection. Front Pharmacol 2021;11. doi: 10.3389/fphar. 2020.600369.  Back to cited text no. 54
He L, Ding Y, Zhang Q, Che X, He Y, Shen H, et al. Expression of elevated levels of pro-inflammatory cytokines in SARS-CoV-infected ACE2+cells in SARS patients: Relation to the acute lung injury and pathogenesis of SARS. J Pathol 2006;210:288-97.  Back to cited text no. 55
Min CK, Cheon S, Ha NY, Sohn KM, Kim Y, Aigerim A, et al. Comparative and kinetic analysis of viral shedding and immunological responses in MERS patients representing a broad spectrum of disease severity. Sci Rep 2016;6:25359.  Back to cited text no. 56
Wong CK, Lam CW, Wu AK, Ip WK, Lee NL, Chan IH, et al. Plasma inflammatory cytokines and chemokines in severe acute respiratory syndrome. Clin Exp Immunol 2004;136:95-103.  Back to cited text no. 57
Al-Abdallat MM, Payne DC, Alqasrawi S, Rha B, Tohme RA, Abedi GR, et al. Hospital-associated outbreak of Middle East respiratory syndrome coronavirus: A serologic, epidemiologic, and clinical description. Clin Infect Dis 2014;59:1225-33.  Back to cited text no. 58
Li G, Chen X, Xu A. Profile of specific antibodies to the SARS-associated coronavirus. N Engl J Med 2003;349:508-9.  Back to cited text no. 59
Hou H, Wang T, Zhang B, Luo Y, Mao L, Wang F, et al. Detection of IgM and IgG antibodies in patients with coronavirus disease 2019. Clin Transl Immunol 2020;9:e01136.  Back to cited text no. 60
Jayamohan H, Lambert CJ, Sant HJ, Jafek A, Patel D, Feng H, et al. SARS-CoV-2 pandemic: A review of molecular diagnostic tools including sample collection and commercial response with associated advantages and limitations. Anal Bioanal Chem 2021;413:49-71.  Back to cited text no. 61
Borges L, Pithon-Curi TC, Curi R, Hatanaka E. COVID-19 and neutrophils: The relationship between hyperinflammation and neutrophil extracellular traps. Mediators Inflamm 2020;2020:8829674. doi: 10.1155/2020/8829674.  Back to cited text no. 62
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 Coronavirus-19 (COVI-19 or SARS-CoV-2): Anti-inflammatory strategies. J Biol Regul Homeost Agents 2020;34:327-31.  Back to cited text no. 63
Dosch SF, Mahajan SD, Collins AR. SARS coronavirus spike protein-induced innate immune response occurs via activation of the NF-κB pathway in human monocyte macrophages in vitro. Virus Res 2009;142:19-27.  Back to cited text no. 64
Aboudounya MM, Heads RJ. COVID-19 and toll-like receptor 4 (TLR4): SARS-CoV-2 may bind and activate TLR4 to increase ACE2 expression, facilitating entry and causing hyperinflammation. Mediators Inflamm 2021;2021:8874339. doi: 10.1155/2021/8874339.  Back to cited text no. 65
Veras FP, Pontelli MC, Silva CM, Toller-Kawahisa JE, de Lima M, Nascimento DC, et al. SARS-CoV-2-triggered neutrophil extracellular traps mediate COVID-19 pathology. J Exp Med 2020;217:e20201129. doi: 10.1084/jem. 20201129.  Back to cited text no. 66
Irani S, Barati I, Badiei M. Periodontitis and oral cancer-current concepts of the etiopathogenesis. Oncol Rev 2020;14:465.  Back to cited text no. 67
Rizzo P, Dalla Sega FV, Fortini F, Marracino L, Rapezzi C, Ferrari R. COVID-19 in the heart and the lungs: Could we “Notch” the inflammatory storm? Basic Res Cardiol 2020;115:31.  Back to cited text no. 68
Schett G, Sticherling M, Neurath MF. COVID-19: Risk for cytokine targeting in chronic inflammatory diseases? Nat Rev Immunol 2020;20:271-2.  Back to cited text no. 69
Heijink IH, Vellenga E, Borger P, Postma DS, de Monchy JG, Kauffman HF. Interleukin-6 promotes the production of interleukin-4 and interleukin-5 by interleukin-2-dependent and -independent mechanisms in freshly isolated human T cells. Immunology 2002;107:316-24.  Back to cited text no. 70
Baseler LJ, Falzarano D, Scott DP, Rosenke R, Thomas T, Munster VJ, et al. An acute immune response to middle east respiratory syndrome coronavirus replication contributes to viral pathogenicity. Am J Pathol 2016;186:630-8.  Back to cited text no. 71
Zhang YY, Li BR, Ning BT. The comparative immunological characteristics of SARS-CoV, MERS-CoV, and SARS-CoV-2 coronavirus infections. Front Immunol 2020;11:2033.  Back to cited text no. 72
İnandıklıoğlu N, Akkoc T. Immune responses to SARS-CoV, MERS-CoV and SARS-CoV-2. In: Turksen K, editor. Cell Biology and Translational Medicine, Volume 9: Stem Cell-Based Therapeutic Approaches in Disease. Cham: Springer International Publishing; 2020. p. 5-12.  Back to cited text no. 73
Booz GW, Altara R, Eid AH, Wehbe Z, Fares S, Zaraket H, et al. Macrophage responses associated with COVID-19: A pharmacological perspective. Eur J Pharmacol 2020;887:173547. doi: 10.1016/j.ejphar. 2020.173547.  Back to cited text no. 74
Haick AK, Rzepka JP, Brandon E, Balemba OB, Miura TA. Neutrophils are needed for an effective immune response against pulmonary rat coronavirus infection, but also contribute to pathology. J Gen Virol 2014;95:578-90.  Back to cited text no. 75
Law HK, Cheung CY, Ng HY, Sia SF, Chan YO, Luk W, et al. Chemokine up-regulation in SARS-coronavirus–infected, monocyte-derived human dendritic cells. Blood 2005;106:2366-74.  Back to cited text no. 76
Jafarzadeh A, Chauhan P, Saha B, Jafarzadeh S, Nemati M. Contribution of monocytes and macrophages to the local tissue inflammation and cytokine storm in COVID-19: Lessons from SARS and MERS, and potential therapeutic interventions. Life Sci 2020;257:118102. doi: 10.1016/j.lfs. 2020.118102.  Back to cited text no. 77
Ahmed F, Jo D-H, Lee S-H. Can natural killer cells be a principal player in Anti-SARS-CoV-2 immunity? Front Immunol 2020;11. doi: 10.3389/fimmu. 2020.586765.  Back to cited text no. 78
Lagunas-Rangel FA. Neutrophil-to-lymphocyte ratio and lymphocyte-to-C-reactive protein ratio in patients with severe coronavirus disease 2019 (COVID-19): A meta-analysis. J Med Virol 2020;92:1733-4.  Back to cited text no. 79
Sun DW, Zhang D, Tian RH, Li Y, Wang YS, Cao J, et al. The underlying changes and predicting role of peripheral blood inflammatory cells in severe COVID-19 patients: A sentinel? Clin Chim Acta 2020;508:122-9.  Back to cited text no. 80
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. doi: 10.3389/fimmu. 2020.00827.  Back to cited text no. 81
Ganji A, Farahani I, Khansarinejad B, Ghazavi A, Mosayebi G. Increased expression of CD8 marker on T-cells in COVID-19 patients. Blood Cells Mol Dis 2020;83:102437. doi: 10.1016/j.bcmd. 2020.102437.  Back to cited text no. 82
He Z, Zhao C, Dong Q, Zhuang H, Song S, Peng G, et al. Effects of severe acute respiratory syndrome (SARS) coronavirus infection on peripheral blood lymphocytes and their subsets. Int J Infect Dis 2005;9:323-30.  Back to cited text no. 83
Swain SL, McKinstry KK, Strutt TM. Expanding roles for CD4⁺T cells in immunity to viruses. Nat Rev Immunol 2012;12:136-48.  Back to cited text no. 84
Siracusano G, Pastori C, Lopalco L. Humoral immune responses in COVID-19 patients: A window on the state of the art. Front Immunol 2020;11. doi: 10.3389/fimmu. 2020.01049.  Back to cited text no. 85
Chen Z, John Wherry E. T cell responses in patients with COVID-19. Nat Rev Immunol. 2020;20:529-36.  Back to cited text no. 86
Zhang C, Wang XM, Li SR, Twelkmeyer T, Wang WH, Zhang SY, et al. NKG2A is a NK cell exhaustion checkpoint for HCV persistence. Nat Commun 2019;10:1507.  Back to cited text no. 87
Irani S. Emerging insights into the biology of metastasis: A review article. Iran J Basic Med Sci 2019;22:833-47.  Back to cited text no. 88
Abassi Z, Knaney Y, Karram T, Heyman SN. The lung macrophage in SARS-CoV-2 infection: A friend or a foe? Front Immunol 2020;11:1312. doi: 10.3389/fimmu. 2020.01312.  Back to cited text no. 89
Masselli E, Vaccarezza M, Carubbi C, Pozzi G, Presta V, Mirandola P, et al. NK cells: A double edge sword against SARS-CoV-2. Adv Biol Regul 2020;77:100737. doi: 10.1016/j.jbior. 2020.100737.  Back to cited text no. 90
Hemmat N, Derakhshani A, Bannazadeh Baghi H, Silvestris N, Baradaran B, De Summa S. Neutrophils, crucial, or harmful immune cells involved in coronavirus infection: A bioinformatics study. Front Genet 2020;11. doi: 10.3389/fgene. 2020.00641.  Back to cited text no. 91
Reusch N, De Domenico E, Bonaguro L, Schulte-Schrepping J, Baßler K, Schultze JL, et al. Neutrophils in COVID-19. Front Immunol 2021;12. doi: 10.3389/fimmu. 2021.652470.  Back to cited text no. 92
Borges RC, Hohmann MS, Borghi SM. Dendritic cells in COVID-19 immunopathogenesis: Insights for a possible role in determining disease outcome. Int Rev Immunol 2021;40:108-125.  Back to cited text no. 93
Faure E, Poissy J, Goffard A, Fournier C, Kipnis E, Titecat M, et al. Distinct immune response in two MERS-CoV-infected patients: Can we go from bench to bedside? PloS One 2014;9:e88716.  Back to cited text no. 94
Josset L, Menachery VD, Gralinski LE, Agnihothram S, Sova P, Carter VS, et al. Cell host response to infection with novel human coronavirus EMC predicts potential antivirals and important differences with SARS coronavirus. mBio 2013;4:e00165-13.  Back to cited text no. 95
Qian Z, Travanty EA, Oko L, Edeen K, Berglund A, Wang J, et al. Innate immune response of human alveolar type II cells infected with severe acute respiratory syndrome-coronavirus. Am J Respir Cell Mol Biol 2013;48:742-8.  Back to cited text no. 96
Cheung CY, Poon LL, Ng IH, Luk W, Sia SF, Wu MH, et al. Cytokine responses in severe acute respiratory syndrome coronavirus-infected macrophages in vitro: Possible relevance to pathogenesis. J Virol 2005;79:7819-26.  Back to cited text no. 97
Chu H, Zhou J, Wong BH, Li C, Cheng ZS, Lin X, et al. Productive replication of Middle East respiratory syndrome coronavirus in monocyte-derived dendritic cells modulates innate immune response. Virology 2014;454-455:197-205.  Back to cited text no. 98
Jiang L, Wang N, Zuo T, Shi X, Poon K-MV, Wu Y, et al. Potent neutralization of MERS-CoV by human neutralizing monoclonal antibodies to the viral spike glycoprotein. Sci Transl Med 2014;6:234ra59-ra59.  Back to cited text no. 99
Liu I-J, Hsueh P-R, Lin C-T, Chiu C-Y, Kao C-L, Liao M-Y, et al. Disease-specific B cell epitopes for serum antibodies from patients with severe acute respiratory syndrome (SARS) and serologic detection of SARS antibodies by epitope-based peptide antigens. J Infect Dis 2004;190:797-809.  Back to cited text no. 100
Nielsen SC, Yang F, Hoh RA, Jackson KJ, Roeltgen K, Lee JY, et al. B cell clonal expansion and convergent antibody responses to SARS-CoV-2. Res Sq [Preprint] 2020. doi: 10.21203/rs. 3.rs-27220/v1.  Back to cited text no. 101
Meng L, Hua F. Coronavirus disease 2019 (COVID-19): Emerging and future challenges for dental and oral medicine. J Dent Res 2020;99:481-7.  Back to cited text no. 102
Peng L, Liu J, Xu W, Luo Q, Chen D, Lei Z, et al. SARS-CoV-2 can be detected in urine, blood, anal swabs, and oropharyngeal swabs specimens. J Med Virol 2020;92:1676-80.  Back to cited text no. 103
To KK-W, Tsang OT-Y, Yip CC-Y, Chan K-H, Wu T-C, Chan JM-C, et al. Consistent detection of 2019 novel coronavirus in saliva. Clin Infect Dis 2020;71:841-3.  Back to cited text no. 104
Chen L, Zhao J, Peng J, Li X, Deng X, Geng Z, et al. Detection of 2019-nCoV in saliva and characterization of oral symptoms in COVID-19 patients. 2020. SSRN 3556665. Available from: https://ssrn.com/abstract=3557140.  Back to cited text no. 105
Karimi S, Arabi A, Shahraki T, Safi S. Detection of severe acute respiratory syndrome Coronavirus-2 in the tears of patients with Coronavirus disease 2019. Eye 2020;34:1220-3.  Back to cited text no. 106
Khatami F, Saatchi M, Zadeh SST, Aghamir ZS, Shabestari AN, Reis LO, et al. A meta-analysis of accuracy and sensitivity of chest CT and RT-PCR in COVID-19 diagnosis. Sci Rep 2020;10:22402.  Back to cited text no. 107
Liu J, Babka AM, Kearney BJ, Radoshitzky SR, Kuhn JH, Zeng X. Molecular detection of SARS-CoV-2 in formalin-fixed, paraffin-embedded specimens. JCI Insight 2020;5:e139042.  Back to cited text no. 108
Yuan X, Yang C, He Q, Chen J, Yu D, Li J, et al. Current and perspective diagnostic techniques for COVID-19. ACS Infect Dis 2020;6:1998-2016.  Back to cited text no. 109
Chang M-S, Lu Y-T, Ho S-T, Wu C-C, Wei T-Y, Chen C-J, et al. Antibody detection of SARS-CoV spike and nucleocapsid protein. Biochem Biophys Res Commun 2004;314:931-6.  Back to cited text no. 110
Böger B, Fachi MM, Vilhena RO, Cobre AF, Tonin FS, Pontarolo R. Systematic review with meta-analysis of the accuracy of diagnostic tests for COVID-19. Am J Infect Control 2021;49:21-9.  Back to cited text no. 111
Udugama B, Kadhiresan P, Kozlowski HN, Malekjahani A, Osborne M, Li VYC, et al. Diagnosing COVID-19: The disease and tools for detection. ACS Nano 2020;14:3822-35.  Back to cited text no. 112
Wang W, Xu Y, Gao R, Lu R, Han K, Wu G, et al. Detection of SARS-CoV-2 in different types of clinical specimens. JAMA 2020;323:1843-4.  Back to cited text no. 113
Zitek T. The appropriate use of testing for COVID-19. West J Emerg Med 2020;21:470-2.  Back to cited text no. 114
Chan KH, Poon LL, Cheng VC, Guan Y, Hung IF, Kong J, et al. Detection of SARS coronavirus in patients with suspected SARS. Emerg Infect Dis 2004;10:294-9.  Back to cited text no. 115
Farooq HZ, Davies E, Ahmad S, Machin N, Hesketh L, Guiver M, et al. Middle East respiratory syndrome coronavirus (MERS-CoV)-Surveillance and testing in North England from 2012 to 2019. Int J Infect Dis 2020;93:237-44.  Back to cited text no. 116
Huang P, Wang H, Cao Z, Jin H, Chi H, Zhao J, et al. A rapid and specific assay for the detection of MERS-CoV. Front Microbiol 2018;9:1101.  Back to cited text no. 117
Modjarrad K. Treatment strategies for Middle East respiratory syndrome coronavirus. J Virus Erad 2016;2:1-4.  Back to cited text no. 118
Conti P, Ronconi G, Caraffa A, Gallenga C, Ross R, Frydas I, et al. Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): Anti-inflammatory strategies. J Biol Regul Homeost Agents 2020;34:327-331.  Back to cited text no. 119
Sheahan TP, Sims AC, Leist SR, Schäfer A, Won J, Brown AJ, et al. Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV. Nat Commun 2020;11:222.  Back to cited text no. 120
de Candia P, Prattichizzo F, Garavelli S, Matarese G. T cells: Warriors of SARS-CoV-2 infection. Trends Immunol 2021;42:18-30.  Back to cited text no. 121
Kritas SK, Ronconi G, Caraffa A, Gallenga CE, Ross R, Conti P. Mast cells contribute to coronavirus-induced inflammation: New anti-inflammatory strategy. J Biol Regul Homeost Agents 2020;34:9-14.  Back to cited text no. 122
Dziedzic A, Wojtyczka R. The impact of coronavirus infectious disease 19 (COVID-19) on oral health. Oral Dis 2020;27:703-6.  Back to cited text no. 123
Runfeng L, Yunlong H, Jicheng H, Weiqi P, Qinhai M, Yongxia S, et al. Lianhuaqingwen exerts anti-viral and anti-inflammatory activity against novel coronavirus (SARS-CoV-2). Pharmacol Res 2020;156:104761. doi: 10.1016/j.phrs. 2020.104761.  Back to cited text no. 124
Selvaraj V, Dapaah-Afriyie K, Finn A, Flanigan TP. Short-term dexamethasone in Sars-CoV-2 patients. R I Med J (2013) 2020;103:39-43.  Back to cited text no. 125
Dai L, Gao GF. Viral targets for vaccines against COVID-19. Nat Rev Immunol 2021;21:73-82.  Back to cited text no. 126
Marian AJ. Current state of vaccine development and targeted therapies for COVID-19: Impact of basic science discoveries. Cardiovasc Pathol 2021;50:107278. doi: 10.1016/j.carpath. 2020.107278.  Back to cited text no. 127
Polack FP, Thomas SJ, Kitchin N, Absalon J, Gurtman A, Lockhart S, et al. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine. N Engl J Med 2020;383:2603-15.  Back to cited text no. 128


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