key: cord-0860756-qk1izkyt
authors: Dezfuli, Neda K.; Adcock, Ian M; Montazami, Nooshin; Mortaz, Esmaeil; Velayati, Aliakbar
title: Update on Immunology of COVID-19 Disease and Potential Strategy for Controlling
date: 2020-12-03
journal: Tanaffos
DOI: nan
sha: 0e219ab5ebf201f257161689db0f4a6aa7beb2b4
doc_id: 860756
cord_uid: qk1izkyt

Coronavirus disease 2019 (COVID-19) is caused by a novel form of the coronavirus that caused severe acute respiratory syndrome (SARS). SARS-CoV-2 raised in China and has broadcast to 261 countries globally. SARS-CoV-2 a member of β-coronavirus family and has an almost matching genome sequence to a bat coronavirus, pointing to the bat as the natural host before it was transmitted to humans. SARS-CoV-2 uses the same receptor, angiotensin-converting enzyme 2 (ACE2) as that used by SARS-CoV and principally infects the respiratory tract. The clinical symptoms of COVID-19 patients include fever, cough and fatigue whilst small populations of patients have gastrointestinal symptoms. The old people and people with underlying metabolic and cardiovascular diseases are more affected to infection and have worse outcomes. These may be associated with acute respiratory distress syndrome (ARDS) and a cytokine storm. In this review, we discuss the pathogenesis and clinical characteristics of disease and the pharmacologic approaches that may control COVID-19.

Tanaffos 2020; 19 (4) : [274] [275] [276] [277] [278] [279] [280] [281] [282] [283] [284] [285] [286] [287] [288] [289] [290] these help exacerbate inflammatory responses in severe patients (4) .

The most common symptoms for COVID-19 infection are polypnea, fever, dry cough, expectoration and nausea/vomiting, fatigue/myalgia and headache with lymphopenia and acute respiratory distress syndrome (ARDS) with pulmonary ground-glass background occurring in severe patients (5) . A reduction in the ability to smell distinct from anosmia is considered a major marker of SARS-CoV-2 infection (6) . 

The viral structure was first reported by Chinese scientists on 7 January 2020 (2) . SARS-CoV-2 was 100nm in size and belonged to the β-coronavirus family and caused the third severe zoonotic coronavirus disease after SARS and MERS (5, 7, 8) . CoVs are also found in animals such as birds and wild mammals. Four genera of the virus have been characterized so far: , ,  and  CoVs (9) . Human CoVs (HCoVs) include 229E, OC43, HKU1, NL63, SARS-CoV, MERS-CoV (10) . 229E and NL63 are two members of the CoV family whilst the others are  family members (10) . CoVs are RNA viruses with a polycistronic genome of ~30kb in size that codes for multiple non-structural proteins such as ORF1a and ORF1b. They also encode some multiple structural proteins including spike (S), envelope (E), membrane (M) and nucleocapsid (N) proteins and lineage-specific accessory proteins including ORF3a, ORF3b, ORF6, ORF7a, ORF7b, ORF8a, ORF8b and ORF9b in SARS-CoV (3, 10) . Main differences between SARS-COV-2 and other CoVs have been described in ORF3b and ORF8 (11) . Both SARS-CoV and MERS-CoV are mainly pathogenic and cause acute respiratory distress syndrome (ARDS) whereas 229E, OC43, HKU1 and NL63 cause the common cold (10) .

The S protein has two parts, S1 and S2, and is a essential immunodominant protein for coronaviruses (2) . S1 is associated with virus-host range and cellular tropism as it possesses the receptor-binding domain (RBD) whilst S2 is responsible for virus-cell membrane fusion via heptad repeat (HR1 and HR2) domains.

RBD in SARS-CoV S1 recognizes angiotensin converting enzyme 2 (ACE2). The RBD continuously moves between a receptor binding stand-up position and a lie-down position for immune evasion (12) By masking the RBD domain from neutralizing antibodies, this bias towards the lying state can favor SARS-CoV-2 to immune evasion (13) . S1 protein in corona viruses has two domain N-terminal (S1-NTD) and C-terminal (S1-CTD) domains. S1-NTDs are responsible for binding sugar and S1-CTDs recognize ACE2, APN, and DPP4 receptors (14) .

The M protein is the viral protein that gives a shape to the viral envelope by binding to the N protein and acting as a central core for coronavirus assembly. M proteins are extremely diverse with respect to amino acid sequence across viruses but maintain structural similarity (2, 3) . The E protein plays a key role in the pathogenesis, assembly, and release of the virus. It is a small integral membrane polypeptide that acts as ion-channel. The N protein, as described above, interacts with the M protein during virion assembly and also increases transcription efficiency of the virus. Besides, the most significant structural proteins, the SARS-CoV-2 genome contain 15 non-structural proteins (NSPs). (Figure 1 ). SARS-CoV-2 has a high binding affinity between the HR1 and HR2 domains that induce simple viral membrane fusion and augment viral infectivity or transmissibility.

Furthermore, the binding affinity between ACE2 and RBD in S protein of SARS-CoV-2 is almost 10-fold higher than that of SARS-CoV which also enhances infectivity and transmissibility (21) . Finally, the vesicles that carry viral particle fuse with the plasma membrane and release (2, 10) . SARS-CoV-2 genomes analysis shows two types of SARS-CoV-2: an L type (~70%) and an S type (~30%) (27) .

The S type of virus is an ancestral version and less aggressive whilst the L type was more common in the early phase of the outbreak in Wuhan but its frequency decreased early in 2020 (27) . A missense mutation in SARS-CoV-2 has significant association with a difference in asymptomatic and symptomatic patients (28) . The lung injury is more obvious in sever patients, which is correlation with a cytokine storm. (49) . This latter scenario is supported by the association between the number of viral particle numbers and COVID-19 severity (50) . This may also accounts for the deaths of healthcare workers who have been exposed to high dose of SARS-CoV-2 (50).

As mentioned above treatment with ACE inhibitors or angiotensin receptor blockers may be trigger expression of ACE2 receptor (47) . Both treatments approaches are general in adults with hypertension, but much less useful in children (47) . Interestingly, children are not less prone to severe ARDS during respiratory tract infections than adults (51) .

The gut microbiota features also represents a risk factor for susceptibility to COVID-19 due to their correlation with proinflammatory cytokine expression (52) . Microbiota play an essential role in pulmonary immune development.

Alterations in gut microbiota (dysbiosis) by antibiotic use or nutrition style can increase respiratory diseases risk (53) .

and neurodegenerative diseases (54 

Diagnosis of SARS-CoV-2 (COVID-19) is on the basis of RNA tests using real-time RT-PCR or next-generation sequencing (3). SARS-CoV-2 RNA is detectable in throat swabs, nasal swabs, sputum, BALF, stool, and blood.

Sampling of the lower respiratory tract by BALF aspirate is recommended due to its higher positivity rate and higher Baricitinib, a pan JAK1 and JAK2 inhibitor and an AAK1

inhibitor, is a candidate COVID-19 treatment as it is relative safety and has a high affinity. Therapeutic dosing with either 2mg or 4mg once daily gave a plasma concentration sufficient for target inhibition (96) .

However, JAK1 inhibitors block IFN-α production and may not, therefore, be suitable for the treating the cytokine storm (62, 76) .

Fedratinib is a JAK2 inhibitor can inhibit secretion of Th17 cytokines and probably IL-6 effects on other cell types, and may prevent the TH17-associated cytokine storm (76) . JAK2 inhibitors can also be used with other anti-viral treatments. As JAK2 inhibition is reversible, acute treatment before the disease transition from serious to critical or during the critical phase would not be expected to affect TH17 activation , which is necessary to maintain innate immunity and response to extracellular pathogens (76) . Tranilast is a tryptophan analogue and can inhibit NLRP3.

Disulfiram is a potent inhibitor of pyroptosis cytokines and further studies need to be conducted (98) .

Melatonin is an immunomodulatory agent and has some efficacy in sever patients by decreasing vessel permeability, anxiety, sedation, and improving sleeping quality (60) . Melatonin has both anti-inflammatory and anti-oxidative effects and potentiates the immune response and, therefore, has indirect anti-viral effects (60) . Sirtuin-1 (SIRT1) mediates the anti-inflammatory actions of melatonin and reduces melatonin-induced skewing of macrophages to the pro-inflammatory phenotype (99) . TMPRSS2 inhibitors can be divided into two groups.

The first include drugs already approved by the FDA or other organizations for treatment of different diseases, including: Camostat, aprotinin and rimantadine (20) .

Camostat mesylate, an approved agent in Japan for the treatment of pancreatitis, inhibits SARS-COV-2 lung cell entry by inhibiting TMPRSS2 (108) . Nafamostat mesylate is another TMPRSS2 inhibitor that is approved in several countries (24) . The second group includes potential drugs not yet approved for the human use, including plasminogen activator inhibitor type 1 (PAI-1). Finally, derivatives of sulfonylated 3-amindinophenylalanylamide were found to inhibit TMPRSS2 with a high efficiently block the influenza virus transmition in human cells (20) . 

The mechanism underlying the cytokine storm induced by COVID-19 is unclear and may be under genetic control.

The reason for the comparative resistance of young children to COVID-19 is unanswered but may reflect an under-developed immune reaction compared to that seen in adults.

Underlying disorders such as diabetes and hypertension are associated with an increased susceptibility to develop more serious illness requiring hospital admission and invasive ventilation.

Furthermore, COVID-19 patients with comorbidities such as previous cardiovascular and/or metabolic diseases are as high risk for the developing severe form of disease.

In addition there is a genetic link between COVID-19 and ACE2 polymorphisms in disorders such as diabetic mellitus, cardiac diseases in Asian populations (110) .

In summary, the immune response by the host is the 

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