Major highlights on SARS-CoV-2 responsible for Coronavirus disease 2019 (COVID-19)

        Classification of Coronavirus:
         Order:              Nidovirales
         Family:            Coronaviridae
         Sub-family:     Coronavirinae
         Genera:           Alphacoronavirus e.g. HCoV-229E, HCoV-NL63
         Betacoronavirus e.g. SARS-CoV, HCoV-HKU1,       
                                             HCoV-OC43, MERS-CoV, SAR-CoV-2
         Gamacoronavirus
         Deltacoronavirus
      
Characteristics of Coronaviruses:
  • Coronaviruses carry the largest genome (26-32kb) among all RNA virus families.
  • Includes enveloped and non-segmented viruses.
  • Single-stranded positive-sense RNA viruses (meaning their RNA can directly act as a template during replication)
  • Crown-like surface projection in electron microscopy endowed the name coronavirus.
  • Helical Nucleocapsid Symmetry
  • Gamma- and delta coronavirus generally affects birds and some can also infect animals.
  • Alpha- and betacoronavirus predominantly infect humans and animals.
  • Human coronaviruses (HCoVs) primarily cause a variety of respiratory tract infections (Weiss and Navas-Martin 2005).
  • HCoV-229E, HCoV-NL63, SARS-CoV, HCoV-HKU1, HCoV-OC43, MERS-CoV and SARS-CoV-2 are medically important human coronaviruses.
  • SARS-CoV and MERS are of bat origin
  • Intermediate host of SARS-CoV: Civet Cats
  • Intermediate host of MERS: Dromedary Camels     
      SARS-CoV-2 salient features:
  • SAR-CoV-2 is probably of bat origin. However, the intermediate host is unknown (although Pangolins???? are predicted to be its host) (Lam et al 2020). 
  •  Sequence homology with SARS-CoV is 80% and that with MERS is 50%.
  • Sequence identity with two bat-derived SARS-like coronavirus bat-SL-CoVZC45 and bat-SL-CoVZXC21= 88%.
  • Primary protease identity between SARS-CoV-2 and SARS-CoV is 96% while that of spike (S) proteins S2 subunit exhibits 89.8% sequence identity (Zhou et al 2020).
  • Absence of 8a protein and fluctuation in the number of amino acids in the 8b and 3c protein in SARS-CoV-2 than compared to SARS-CoV.
  • SARS-CoV-2 causes a disease called Coronavirus disease 2019 (COVID-19).
  • Host cell receptor: Angiotensin-converting enzyme 2 (ACE2)
  • The basic reproduction number (R0) measures the transmissibility of the disease by SARS-CoV-2.
  • R0 is an indication of the transmissibility of a virus, representing the average number of new infections generated by an infectious person in a totally naive population (unexposed population).
  • Significance of R0: For R0 > 1, the number infected is likely to increase, and for R0 < 1, the transmission is likely to die out.

Table 1: Comparsion of basic reproduction number (Ro)

Study Location Average Ro
Joseph et al. China 3.58
Imai 2020 Wuhan 2.5
Tang et al 2020 China 6.47
Qun Li et al 2020 China 2.2
Shen et al 2020 Wuhan 6.49
Liu et al 2020a China and overseas 2.90
Liu et al 2020b China and overseas 2.92
Read et al 2020 China 3.11
Majumder et al 2020 Wuhan 2.55
WHO 2020 China 2.24
Cao et al 2020 China 4.08
Zhao et al 2020a China 2.24
Zhao et al 2020b China 3.58
          Comparison of Estimated R0 value in SARS, MERS, and SARS-CoV-2
  • Estimated R0 value for SARS=3
  • Estimated R0 value for SARS=0.45-8.1 (Saudi Arabia to South Korea)
  • Estimated basic reproduction number (R0) value for SARS-CoV-2 varies as per studies in different endemic settings.
  • A study estimated the range of (R0) ranged from 1.4 to 6.49, with a mean of 3.28, a median of 2.79 and an interquartile range (IQR) of 1.16. The data are tabulated below (Table 1).   
  • Probable reasons for the rapid spread of COVID-19: Viral transmission through feco-oral route, aerosol formation (droplet infection) and circulation through the asymptomatic carrier.
  • Clinical features: Form mild to severe acute respiratory disease
  • Most frequent manifestation: Pneumonia characterized by fever, cough, dyspnea (difficulty in breathing) and bilateral infiltrates on chest imaging.
  • Incubation Period: 2-14 days
  • However, a research group at Guangzhou Medical University reported the incubation period to be 24 days.
  • The onset of fever and respiratory symptoms occurred approximately 3 to 6 days after presumptive exposure in an infected family cluster (Rothe et al 2020).

          Diagnostic Testing:
  • Specimen: Nasopharyngeal and Oropharyngeal Swabs (use of PPE during sample collection)
  • Storage: 4oC in less than 72 hours. If delay is anticipated for more than 72 hours: -80oC 
  • Shipment: On dry ice or liquid nitrogen to the laboratory. 
  •       Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) that uses 
    primers and probes designed to detect a variety of targets in the SARS-CoV-2 genomes: RRdRP gene (encodes RNA dependent RNA polymerase enzyme), E gene (encodes envelope protein) and N gene (encodes nucleocapsid protein). 
  • The sensitivity and specificity of the tests are not widely known.
  • So, multiple specimen testing is recommended (CDC 2020).
  • Commercial rapid kit-test are also available to detect IgM and IgG antibodies against SARS-CoV-2.
  • CDC and WHO recommend viral isolation (culture) be done only in laboratories privileged with Bio-safety level-3 (BSL-3).
          Treatment:
  • Supportive treatment based on disease symptoms.
  • No promising antiviral treatments are available. However, Remdesivir and Hydroxychloroquine are widely used repurposed drugs for alleviating severity.
  • Compounds proven effective against SARS-CoV and MERS-CoV have not been tested widely for the newly emerged SARS-CoV-2 (Khan et al 2020).
  • Therapeutic management is done to improve the immune response.
  • Effective drugs in vitro: Remdesivir and chloroquine (Wang et al 2020).
  • Treatment with remdesivir alone or in combination with chloroquine or interferon beta was found effective against COVID-19 infection without any side effects (Holshue et al 2020; Sheahan et al 2020; Wang et al 2020).
  • Antiviral agents targeting nucleosides, nucleotides, viral nucleic acids, and enzymes/proteins involved in the replication and transcription of coronaviruses can be promising strategies to treat coronavirus diseases including COVID-19 (Table 2).
  • Targeting the structural genes could be an effective therapeutic strategy against coronaviruses (Zumla et al 2016).

Table 2: Drugs proposed against the SARS-CoV-2

Name of Drugs Mode of Action Reference
Arbidol Blocks virus entry into cells Fink et al 2018
Aryl diketoacids (Adks) Target helicase to inhibit its unwinding Zumla et al 2016
Bananins Target helicase to inhibit unwinding and activity of ATPase Zumla et al 2016
Bcx4430 GTargets RdRp (RNA-dependent RNA polymerase) enzyme to inhibit synthesis of viral RNA synthesis and capping of mRNA Pruijssers and Denison 2019
Chloroquine *Antiviral activity by increasing pH of intracellular vacuoles and altering protein degradation pathways results in interfering virus/cell fusion and glycosylation of cellular receptors.
*Immunomodulatory effects may lead to reduction in pro-inflammatory cytokines.
*Inhibits glycosylation of the cellular ACE2 receptor and block binding of the virus to the cell receptorBlocks virus entry into cells.		 Liu et al 2020
Cyclosporine, alisporivir Inhibit cyclophilin to affect calcineurin–NFAT pathway Zumla et al 2016
Dasatinib Inhibits kinase signaling associated pathways to block viral entry Zumla et al 2016
dsRNA-activated caspase oligomerizer (DRACO) Targets viral dsRNA to induce apoptosis in cells containing virus Baez-Santos et al 2015 and Mielech et al 2019
Griffithsin Targets oligosaccharides on S to block viral binding with host cell Barton et al 2014
Hexamethylene amiloride Targets viral envelope to inhibit ion channel activity Pervushin et al 2009
Hydroxychloroquine *Antiviral activity by increasing pH of intracellular vacuoles and altering protein degradation pathways results in interfering virus/cell fusion and glycosylation of cellular receptors.
*Immunomodulatory effects may lead to reduction in pro-inflammatory cytokines.		 Liu et al 2020
Imatinib Same as Dasatinib. Zumla et al 2016
Interferon- α Immunomodulatory properties
Ivermectin (FDA-approved antiparasitic drug) Inhibits the replication of SARS-CoV-2 in vitro.
It binds to and destabilises the Impα/β1 heterodimer by preventing Impα/β1 from binding to the viral protein and prevents it from entering the nucleus of host cell and enhances antiviral response.
Bananins Target helicase to inhibit unwinding and activity of ATPase Caly et al 2020
Jl103 Targets lipid membrane and causes modification of phospholipids Totura and Bavari 2019 and Zumla et al 2016
K22 *Targets membrane-bound replication complexes of virus in host cell to inhibit RNA synthesis Momattin et al 2019
Lopinavir/ Ritonavir Targets 3C like protease (3CLpro) enzyme to inhibit its activity Totura and Bavari 2019
Niclosamide Neutralization of endosomal pH. Jung et al 2019
Nitazoxanide Induces the innate interferon responses against viral pathogens Shakya et al 2018
Rapamycin Same as Dasatinib. Ma-Lauer et al 2020 and Zumla et al 2016
Recombinant interferons Induce the innate interferon responses against viral pathogens Totura and Bavari 2019 and Zumla et al 2016
Remdesivir Early termination of viral RNA transcription at prematured stage Sheahan et al 2020
Ribavirin Same as Bcx4430. Sheahan et al 2020 and Totura and Bavari 2019
         Vaccines:
  • Licensed vaccines are not available.
  • Vaccine development is going on and few vaccines are under clinical trial. 
          Safety Approaches to break the Chain:
  • Staying at home maintaining regular hand hygiene.
  • Use of flexed elbow or tissue paper during sneezing and coughing and safe disposal.
  • Use of alcohol-based sanitizer having >60% alcohol.
  • Use of N95 masks and PPE by dedicated health workers in the frontline.
    Viability of the virus:
  • COVID-19 virus can survive for up to 72 hours on plastic and stainless steel, less than 4 hours on copper, and less than 24 hours on cardboard (WHO).                              
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