The Open Public Health Journal




ISSN: 1874-9445 ― Volume 14, 2021
REVIEW ARTICLE

A Causal not Casual Approach to Coronavirus Disease 19. Tracing the Roots of Novel Virus



Prachet Dakshinkar*, 1, Apoorva Mishra1, Nitin Bhola1, Anendd Jadhav1, Srinivas Reddy2
1 Department of Oral and Maxillofacial Surgery ,Sharad Pawar Dental College and Hospital, Wardha, India
2 Department of Oral and Maxillofacial Surgery ,GSR Institute of Craniofacial and Facial Plastic Surgery, Hyderabad, India

Abstract

Coronavirus disease (COVID-19) has generated extraordinary circumstances worldwide like never before; India is already reeling under the health issues caused by this disease. At this critical juncture, having insights into pathogenesis is important so that unwanted panic and uncertainty regarding causative mechanisms can be curtailed. The causative pathogen of COVID-19 has been identified to be SARS-CoV-2 or also known as novel Coronavirus (nCov), which is a variant of the Coronaviruses (CoV). Through this review, we intend to present phylogenetic analysis of nCoV, epidemiology and pathogenesis of COVID-19. On the basis of nucleotide sequencing, nCoV isolates from China and US were found to have the highest similarity index of about 88.2% with two “Bat-SARS-like CoV (Bat-SL-CoVZC45 and Bat-SL-CoVZXC21. Researchers think that bat might have initiated the outbreak and an unknown wild animal might have acted as an intermediate host prior to the transmission to humans. Nasal cavity is considered to be the entry point for nCoV. Initially, a defined RBD of nCoV will locate the ACE2 receptors of Type II Pneumocytes in the alveoli, and will attach and fuse together to form a receptor host membrane. This critical step is responsible for the susceptibility of the host. Blessing in disguise is that the mutation rate of “nCoV” is much slower than “SARS CoV” and “MERS CoV”. Thus, vaccines and antiviral agents developed will not be rendered ineffective early due to slow genetic drift. The live animal markets act as highly potential centres for spill over of viruses from their reservoirs to other species and in turn humans. Such markets need to be dealt with diligently in the wake of the high risk they pose for such outbreaks.

Keywords: SARS-CoV-2, nCov, COVID-19, MERS CoV, SARS CoV, Acute Respiratory Distress Syndrome (ARDS).


Article Information


Identifiers and Pagination:

Year: 2021
Volume: 14
Issue: Suppl-1, M7
First Page: 149
Last Page: 153
Publisher Id: TOPHJ-14-149
DOI: 10.2174/1874944502114010149

Article History:

Received Date: 21/7/2020
Revision Received Date: 11/12/2020
Acceptance Date: 16/12/2020
Electronic publication date: 22/03/2021
Collection year: 2021

© 2021 Dakshinkar et al

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: https://creativecommons.org/licenses/by/4.0/legalcode. This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


* Address correspondence to this author at the Sharad Pawar Dental College and Hospital, Oral and Maxillofacial Surgery, India; Tel: 9890124992; E-mail:pracdak@gmail.com





1. INTRODUCTION

Coronavirus disease (COVID-19) has generated extraordinary circumstances like never before, world is already reeling under the health issues caused by this disease. This global pandemic has engulfed more than 200 countries and the numbers are still soaring. Reasons for resurgence and transmissibility of coronavirus are varied. At this critical juncture, having insights into pathogenesis is important so that unwanted panic and uncertainty regarding causative mechanisms can be curtailed.

The causative pathogen of COVID-19 has been identified to be SARS-CoV-2, also known as novel Coronavirus (nCov), which is a variant of the Coronaviruses (CoV). The genetic structure of CoV places it in Coronaviridae family with single strands of RNA genome. Corona in Latin means crown and its name is derived due to its spike projections from the virus membrane, which are known to be largest amongst RNA viruses’ genome [1Weiss SR, Navas-Martin S. Coronavirus pathogenesis and the emerging pathogen severe acute respiratory syndrome coronavirus. Microbiol Mol Biol Rev 2005; 69(4): 635-64.
[http://dx.doi.org/10.1128/MMBR.69.4.635-664.2005] [PMID: 16339739]
].

The Coronavirus primarily affects the respiratory system of humans. The first instance of COVID 19 dates back to December 2019 when a few patients with a history of pneumonia were reported. This was the first emergent situation pertaining to nCoV of this decade, which originated from the animal wholesale market in Wuhan, China [2Bogoch A, Watts A, Thomas-Bachli C. Huber, M.U.G. Kraemer, K. Khan. Pneumonia of unknown etiology in Wuhan, China: potential for international spread via commercial air travel. J Travel Med 2020; 27(2): taaa008..
[http://dx.doi.org/10.1093/jtm/taaa008]
]. Origin of COVID 19 has been marred with various conjectures. It is still not clear whether a superspreading event occurred in this market or it was the reason of the initial outbreak.

All coronaviruses have a similar structural genomic expression, which consists of sixteen non-structural proteins followed by four structural proteins viz. Spike (S), Envelope (E), Membrane (M), and Nucleocapsid (N) (Fig. 1). Human Coronavirus (HCoV) are amongst the variants of Cov, which are primarily known to infect humans. These HCoVs are six in number, namely, “HCoV-NL63, Severe Acute Respiratory Syndrome coronavirus (SARS-CoV), HCoV 229E, Middle East Respiratory Syndrome Coronavirus (MERS-CoV), HCoV OC43 and HCoV-HKU1” [3Kin N, Miszczak F, Lin W, Gouilh MA, Vabret A. Genomic analysis of 15 human coronaviruses OC43 (HCoV-OC43s) circulating in france from 2001 to 2013 reveals a high intra-specific diversity with new recombinant genotypes. Viruses 2015; 7(5): 2358-77.
[http://dx.doi.org/10.3390/v7052358] [PMID: 26008694]
]. Phylogenetically CoV has four generations, namely “Alpha-CoV, Beta-CoV, Gamma-CoV and Delta-CoV” [4Langereis MA, van Vliet AL, Boot W, de Groot RJ. Attachment of mouse hepatitis virus to O-acetylated sialic acid is mediated by hemagglutinin-esterase and not by the spike protein. J Virol 2010; 84(17): 8970-4.
[http://dx.doi.org/10.1128/JVI.00566-10] [PMID: 20538854]
]. Alpha and Beta forms of CoV infect only

Fig (1)
Depiction of SARS CoV 2 structure.


mammals and are certainly responsible for human respiratory infections and enteric disease in animals. The two major zoonotic pathogenic CoV “SARS-CoV and MERS-CoV” belong to the genus “Beta- CoV”.

The scientific interest in CoV grew after the breakout of SARS in 2002-2003. We intend to present phylogenetic analysis of nCoV, epidemiology and pathogenesis of COVID-19.

2. PHYLOGENETIC ANALYSIS

Human origins could be ascertained due to steps undertaken in knowing the human mitochondrial DNA. It helped us in getting information about movements on the planet before documentation was in place. Therefore, phylogenetic analysis is one of the standard practices for understanding the origin and evolution. This is the time we apply similar concept of phylogeny in understanding the evolution of nCoV.

Literature is based on the evidences related to the “Nucleotide sequencing and S gene pattern” in amino acid based index. On the basis of nucleotide sequencing, the isolates of nCoV, from China and US were found to have the highest similarity index of about 88.2% with two, “Bat-SARS-like CoV (Bat-SL-CoVZC45 and Bat-SL-CoVZXC21)” [5Zhu N, Zhang D, Wang W, et al. A novel coronavirus from patients with pneumonia in China. N Engl J Med 2020; 382(8): 727-33.
[http://dx.doi.org/10.1056/NEJMoa2001017] [PMID: 31978945]
], followed by SARS Cov, which is 70.8% to 74.7%. The similarity descended to about 40.8% to 41.5% with “Canine Respiratory CoV (CRCov)” and “Bovine CoV (BCov)” of the subgenus “Embecovirus”. The “S gene” pattern similarity, for nCoV isolates with Bat SARS-like CoVs varied from 81.2% to 81.8% and for other SARS like CoVs from, 77.0% to 78.1%, respectively [6Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020; 579(7798): 270-3.
[http://dx.doi.org/10.1038/s41586-020-2012-7] [PMID: 32015507]
]. The similarity of nCoV with isolates of HCoV-OC43 was also found to be lower (28.0%). These distinctiveness and variabilities are indicative of a diversified nature of nCov.

The motifs of all nCoV have well modified Receptor binding domain (RBD) and the polybasic cleavage site is considered to be derived from a common predecessor. The nCoV shows divergence based on the phylogeny, despite the similarity to SARS-CoV.

The divergence is attributed mainly to the “S” protein of nCoV, which is particularly distinct from other viruses under the same subgenus Sarbecovirus. The length of the “S” protein is more than the other viruses, and at the N-Terminal region, three short insertions have been detected. Also, in the Receptor binding domain (RBD) of “S” protein four changes are found.

But, the Binding affinity of nCov RBD to Angiotensin Converting Enzyme 2 (ACE2) is found to be significantly higher than the SARS CoV RBD. This serves as the major cause for its extensive transmission from human to human [7Letko M, Marzi A, Munster V. Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses. Nat Microbiol 2020; 5(4): 562-9.
[http://dx.doi.org/10.1038/s41564-020-0688-y] [PMID: 32094589]
].

The contribution of bats for spreading COVID-19 cannot be overlooked but substantial facts regarding the role of an intermediate animal between bats and humans cannot be neglected. In December 2019, when the first outbreak was reported, most bat species were in hibernating phase. Secondly, no bats were for sale in the market. In previous human viruses “SARS-CoV” and “MERS-CoV” another animal served as an intermediate host. The evolutionary relationship between CoV and bats was proposed by some researchers. It was found that the predecessors of SARS-CoV first spread through the bats of the Hipposideridae family, then Rhinolophidae family, then masked palmcivets and eventually humans [8Lau SK. Li Kenneth, Huang Yi, Shek Chung-Tong, Tse Herman, Wang Ming, K. Y. Eco epidemiology and complete genome comparison of different strains of severe acute respiratory syndrome related Rhinolophus bat coronavirus in China reveal bats as a reservoir for acute, self-limiting infection that allows recombination events. J Virol 2010; 84(6): 2808-19.
[http://dx.doi.org/10.1128/JVI.02219-09] [PMID: 20071579]
]. With this information, available researchers think that bat might have initiated the outbreak and an unknown wild animal might have acted as an intermediate host prior to the transmission to humans [9Andersen KG, Rambaut A, Lipkin WI, Holmes EC, Garry RF. The proximal origin of SARS-CoV-2. Nat Med 2020; 26(4): 450-2.
[http://dx.doi.org/10.1038/s41591-020-0820-9] [PMID: 32284615]
].

While, tracing the roots of CoV it was found that Himalayan Civet was the natural host of SARS CoV. Later on, in 2005 an HKU variant in horseshoe bats was identified in Hong Kong. Ever since bats were regarded as the potential reservoir and natural host of SARS CoV [10Jie Cui, Fang Li, Shi Zheng-Li. Origin and evolution of pathogenic coronaviruses. Natures Reviews Microbiology 2019; 17(3): 181-92.].

Virus sampled from Rhinolopus affinis bat resembles 96% to SARS CoV 2 but divergence in its receptor binding domain impairs its precise binding to ACE 2 receptors. Malayan pangolins coronaviruses exhibit stronger kinship to SARS CoV 2 through six key receptor binding domains [9Andersen KG, Rambaut A, Lipkin WI, Holmes EC, Garry RF. The proximal origin of SARS-CoV-2. Nat Med 2020; 26(4): 450-2.
[http://dx.doi.org/10.1038/s41591-020-0820-9] [PMID: 32284615]
, 11Lu R, Zhao X, Li J, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: Implications for virus origins and receptor binding. Lancet 2020; 395(10224): 565-74.
[http://dx.doi.org/10.1016/S0140-6736(20)30251-8] [PMID: 32007145]
].

3. PATHOGENESIS AND EPIDEMIOLOGY OF NCOV

Symptoms caused by nCoV have distinct similarities to those caused by SARS-CoV. There were 8000 confirmed cases and 800 deaths of SARS CoV in 2002-2003. It re-emerged in 2003-2004 but was in milder form, having no human to human transmission [12Peiris JSM, Lai ST, Poon LLM, et al. Coronavirus as a possible cause of severe acute respiratory syndrome. Lancet 2003; 361(9366): 1319-25.
[http://dx.doi.org/10.1016/S0140-6736(03)13077-2]
, 13Liang G, Chen Q, Xu J, et al. Laboratory diagnosis of four recent sporadic cases of community-acquired SARS, Guangdong Province, China. Emerg Infect Dis 2004; 10(10): 1774-81.
[http://dx.doi.org/10.3201/eid1010.040445] [PMID: 15504263]
].

Similar to “SARS-CoV” and “MERS-CoV”, “nCoV” is known to cause respiratory infections in the form of fever, cough, dyspnoea and more severe sequelae like pneumonia, ultimately progressing to Acute Respiratory Distress Syndrome (ARDS) [14Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395(10223): 497-506.
[http://dx.doi.org/10.1016/S0140-6736(20)30183-5] [PMID: 31986264]
]. It is interesting to know the path of the entrance of nCoV in the host cell (Fig. 2). The Spike (S) Protein, in the RBD, which is envelope-anchored facilitates the entry in cells of the host. Nasal cavity is the entry point for nCoV where it binds to epithelial cells and starts multiplying. Innate immune response is restricted at this point of time. Over the course of next few days, it travels down the respiratory tract, during which the clinical features become evident [15Weinheimer VK, Becher A, Tönnies M, et al. Influenza A viruses target type II pneumocytes in the human lung. J Infect Dis 2012; 206(11): 1685-94.
[http://dx.doi.org/10.1093/infdis/jis455] [PMID: 22829640]
]. Further through the trachea-bronchial tree, it reaches up to the alveoli. Initially, a defined RBD of nCoV, will locate the ACE2 receptors of Type II Pneumocytes in the alveoli, and will attach and fuse together to form receptor host membrane. This critical step is responsible for the susceptibility of the host. Once the single stranded genome virus is engulfed, it will lead to series of pathogenic changes. Firstly, it will release the single stranded RNA into the cytoplasm. This RNA uses the host cell ribosome and undergoes translation after which this RNA gets converted into specific polyprotein molecules. Secondly, RNA dependent RNA polymerase will replicate the RNA. Simultaneously, these polyprotein molecules produced are transformed into various viral components by enzyme proteinase. These viral components get combined with the replicated RNAs to produce a number of virus particles.

Fig (2)
Depicting pathogenesis of COVID-19.


In this process of formation of viral components, Type II pneumocytes which are responsible for producing pulmonary surfactant, are destroyed. This again leads to a series of events in which initially inflammatory mediators are released. These mediators will stimulate the Macrophages, which will release Cytokine i.e. IL1, IL6 and TNFα, further causing vasodilation and increases the capillary permeability. Due to this interstitial oedema increases around the alveoli, resulting in its compression. Also, some amount of interstitial fluid enters the alveoli, resulting in alveolar oedema, and damaging the surfactant, further leading to alveolar collapse. This collapse will cause Hypoxemia, and increases the work of breathing. Secondly, during the process of release of inflammatory mediators, Neutrophils released as a first line defence to destroy the viruses will in turn land up, collapsing the alveolus itself. The process starts by the release of Neutrophils, which further stimulate the proteases and reactive oxygen species, which in turn damage the Type I pneumocytes, which has a pivotal role in gaseous exchange. Thus, the cumulative effect leads to diffuse alveolar damage, further promulgating into, acute respiratory distress syndrome (ARDS). Healing in response to this will cause more scarring and fibrosis [16Yee M, Domm W, Gelein R, et al. Alternative Progenitor Lineages Regenerate the Adult Lung Depleted of Alveolar Epithelial Type 2 Cells. Am J Respir Cell Mol Biol 2017; 56(4): 453-64.
[http://dx.doi.org/10.1165/rcmb.2016-0150OC] [PMID: 27967234]
].

Even asymptomatic individuals of nCov have contributed to its spread. In terms of incubation, nCov follows the trends of other human coronaviruses. The nCov can even be detected in faeces but whether it has a role in faeco-oral transmission is still to be ascertained [17Risku M, Lappalainen S, Räsänen S, Vesikari T. Detection of human coronaviruses in children with acute gastroenteritis. J Clin Virol 2010; 48(1): 27-30.
[http://dx.doi.org/10.1016/j.jcv.2010.02.013] [PMID: 20233673]
]. Previously known human coronaviruses are well adapted to humans. For this to happen, adaptive mutations have to be present, which counteract host restriction factors.

Researchers discovered a couple of viral hotspots on ACE2 receptors of Type II pneumocytes of human around which naturally occurring RBM mutations occurred. This played a pivotal role in decoding the host range. The “nCoV” has a distinct capability of identifying homologous gene sequences of ACE2 receptors from a diverse pool of species, except in the species of mouse and rat. This distinct feature for partial viral adaptations stimulated viral replications and promoted the interspecies transmission [18Wu KL, Peng GQ, Wilken M, Geraghty RJ, Li F. Mechanisms of host receptor adaptation by severe acute respiratory syndrome coronavirus. Journal of Biological Chemistry 2012; 287(12): 8904-11.
[http://dx.doi.org/10.1074/jbc.M111.325803]
].

COVID-19 infected individuals have demonstrated higher levels of C-reactive protein (CRP), Erythrocyte sedimentation rate (ESR), D-Dimer. Although the normal CRP is in the range of 0 mg/L to 10 mg/L, but in COVID19 infected individuals, it reaches the tune of 16.16 mg/L [14Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395(10223): 497-506.
[http://dx.doi.org/10.1016/S0140-6736(20)30183-5] [PMID: 31986264]
]. Also, significantly elevated blood levels of Inflammatory mediators such as Cytokines and Chemokines are also noted. Mostly Interleukin (IL1-β,1 RA,7, 8, 9, and 10), Fibroblast Growth factors (FGF- 2), Granulocyte Colony Stimulating Factors (GCSF), Granulocyte Macrophage Colony Stimulating Factor (GMCSF), Interferon Gamma (IFNγ), Interferon Gamma induced Protein (IP10), Monocyte Chemoattractant Protein 1 (MCP1), Macrophage Inflammatory Proteins (MIP1α and MIP1β), Platelet derived Growth Factor subunit B (PDGFB), Tumor Necrosis Factor (TNFα), and Vascular Endothelial Growth Factor (VEGF A) [19Lei J, Li J, Li X, Qi X. CT imaging of the 2019 novel coronavirus (2019-nCoV) pneumonia. Radiology 2020; 295(1): 18.
[http://dx.doi.org/10.1148/radiol.2020200236] [PMID: 32003646]
]. Non-invasive ventilation (NIV) is an emerging tool in treating the patient with Acute hypoxic respiratory failure (AHRF) and can prevent patients landing up in ARDS [20Tendulkar M, Ninave S. Prospective comparison of pressor and airway responses to iv esmolol and iv dexmedetomidine during emergence from general anaesthesia and extubation. JKIMSU 2017; 6(1): 49-56.]. However, patients with severe hypoxia may require assisted ventilation. During the process of intubation, it is a known fact that stimulation of pharyngeal and laryngeal receptors may stimulate the tachycardia and hypertension [21Bajaj A, Kumar S, Inamdar AH, Agrawal L. Noninvasive ventilation in acute hypoxic respiratory failure in medical intensive care unit: A study in rural medical college. Int J Crit Illn Inj Sci 2019; 9(1): 36-42.
[http://dx.doi.org/10.4103/IJCIIS.IJCIIS_40_18] [PMID: 30989067]
], ultimately culminating in ARDS.

The mutation of CoV, in general, is on a higher aspect, when compared to other single stranded RNA viruses. This mutation rate is attributed to a lack of proof reading exoribonucleases [22Su S, Wong G, Shi W, et al. Epidemiology, genetic recombination, and pathogenesis of coronaviruses. Trends Microbiol 2016; 24(6): 490-502.
[http://dx.doi.org/10.1016/j.tim.2016.03.003] [PMID: 27012512]
]. But the blessing in disguise is that the mutation rate of “nCoV” is much slower than “SARS CoV” and “MERS CoV” [23Zhao Z, Li H, Wu X, et al. Moderate mutation rate in the SARS coronavirus genome and its implications. BMC Evol Biol 2004; 4: 21.
[http://dx.doi.org/10.1186/1471-2148-4-21] [PMID: 15222897]
]. Thus, vaccines and antiviral agents developed will not be rendered ineffective early due to slow genetic drift.

CONCLUSION

Coronavirus has resurfaced with the advent of “SARS-CoV-2”. COVID-19 led to unprecedented circumstances, which has put strenuous load on the healthcare services. The economy has come to a standstill. It has infused a sense of fear and uncertainty amongst people. This virus has made us understand the magnanimity of zoonotic diseases and extent to which they can go in putting the human race at risk on all fronts. The live animal markets can act as highly potential centers for spillover of viruses from their reservoirs to other species and in turn humans. Such markets need to be dealt with diligently in the wake of the high risk they pose for such outbreaks.

CONSENT FOR PUBLICATION

Not applicable

FUNDING

None.

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENTS

Declared none.

REFERENCES

[1] Weiss SR, Navas-Martin S. Coronavirus pathogenesis and the emerging pathogen severe acute respiratory syndrome coronavirus. Microbiol Mol Biol Rev 2005; 69(4): 635-64.
[http://dx.doi.org/10.1128/MMBR.69.4.635-664.2005] [PMID: 16339739]
[2] Bogoch A, Watts A, Thomas-Bachli C. Huber, M.U.G. Kraemer, K. Khan. Pneumonia of unknown etiology in Wuhan, China: potential for international spread via commercial air travel. J Travel Med 2020; 27(2): taaa008..
[http://dx.doi.org/10.1093/jtm/taaa008]
[3] Kin N, Miszczak F, Lin W, Gouilh MA, Vabret A. Genomic analysis of 15 human coronaviruses OC43 (HCoV-OC43s) circulating in france from 2001 to 2013 reveals a high intra-specific diversity with new recombinant genotypes. Viruses 2015; 7(5): 2358-77.
[http://dx.doi.org/10.3390/v7052358] [PMID: 26008694]
[4] Langereis MA, van Vliet AL, Boot W, de Groot RJ. Attachment of mouse hepatitis virus to O-acetylated sialic acid is mediated by hemagglutinin-esterase and not by the spike protein. J Virol 2010; 84(17): 8970-4.
[http://dx.doi.org/10.1128/JVI.00566-10] [PMID: 20538854]
[5] Zhu N, Zhang D, Wang W, et al. A novel coronavirus from patients with pneumonia in China. N Engl J Med 2020; 382(8): 727-33.
[http://dx.doi.org/10.1056/NEJMoa2001017] [PMID: 31978945]
[6] Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020; 579(7798): 270-3.
[http://dx.doi.org/10.1038/s41586-020-2012-7] [PMID: 32015507]
[7] Letko M, Marzi A, Munster V. Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses. Nat Microbiol 2020; 5(4): 562-9.
[http://dx.doi.org/10.1038/s41564-020-0688-y] [PMID: 32094589]
[8] Lau SK. Li Kenneth, Huang Yi, Shek Chung-Tong, Tse Herman, Wang Ming, K. Y. Eco epidemiology and complete genome comparison of different strains of severe acute respiratory syndrome related Rhinolophus bat coronavirus in China reveal bats as a reservoir for acute, self-limiting infection that allows recombination events. J Virol 2010; 84(6): 2808-19.
[http://dx.doi.org/10.1128/JVI.02219-09] [PMID: 20071579]
[9] Andersen KG, Rambaut A, Lipkin WI, Holmes EC, Garry RF. The proximal origin of SARS-CoV-2. Nat Med 2020; 26(4): 450-2.
[http://dx.doi.org/10.1038/s41591-020-0820-9] [PMID: 32284615]
[10] Jie Cui, Fang Li, Shi Zheng-Li. Origin and evolution of pathogenic coronaviruses. Natures Reviews Microbiology 2019; 17(3): 181-92.
[11] Lu R, Zhao X, Li J, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: Implications for virus origins and receptor binding. Lancet 2020; 395(10224): 565-74.
[http://dx.doi.org/10.1016/S0140-6736(20)30251-8] [PMID: 32007145]
[12] Peiris JSM, Lai ST, Poon LLM, et al. Coronavirus as a possible cause of severe acute respiratory syndrome. Lancet 2003; 361(9366): 1319-25.
[http://dx.doi.org/10.1016/S0140-6736(03)13077-2]
[13] Liang G, Chen Q, Xu J, et al. Laboratory diagnosis of four recent sporadic cases of community-acquired SARS, Guangdong Province, China. Emerg Infect Dis 2004; 10(10): 1774-81.
[http://dx.doi.org/10.3201/eid1010.040445] [PMID: 15504263]
[14] Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395(10223): 497-506.
[http://dx.doi.org/10.1016/S0140-6736(20)30183-5] [PMID: 31986264]
[15] Weinheimer VK, Becher A, Tönnies M, et al. Influenza A viruses target type II pneumocytes in the human lung. J Infect Dis 2012; 206(11): 1685-94.
[http://dx.doi.org/10.1093/infdis/jis455] [PMID: 22829640]
[16] Yee M, Domm W, Gelein R, et al. Alternative Progenitor Lineages Regenerate the Adult Lung Depleted of Alveolar Epithelial Type 2 Cells. Am J Respir Cell Mol Biol 2017; 56(4): 453-64.
[http://dx.doi.org/10.1165/rcmb.2016-0150OC] [PMID: 27967234]
[17] Risku M, Lappalainen S, Räsänen S, Vesikari T. Detection of human coronaviruses in children with acute gastroenteritis. J Clin Virol 2010; 48(1): 27-30.
[http://dx.doi.org/10.1016/j.jcv.2010.02.013] [PMID: 20233673]
[18] Wu KL, Peng GQ, Wilken M, Geraghty RJ, Li F. Mechanisms of host receptor adaptation by severe acute respiratory syndrome coronavirus. Journal of Biological Chemistry 2012; 287(12): 8904-11.
[http://dx.doi.org/10.1074/jbc.M111.325803]
[19] Lei J, Li J, Li X, Qi X. CT imaging of the 2019 novel coronavirus (2019-nCoV) pneumonia. Radiology 2020; 295(1): 18.
[http://dx.doi.org/10.1148/radiol.2020200236] [PMID: 32003646]
[20] Tendulkar M, Ninave S. Prospective comparison of pressor and airway responses to iv esmolol and iv dexmedetomidine during emergence from general anaesthesia and extubation. JKIMSU 2017; 6(1): 49-56.
[21] Bajaj A, Kumar S, Inamdar AH, Agrawal L. Noninvasive ventilation in acute hypoxic respiratory failure in medical intensive care unit: A study in rural medical college. Int J Crit Illn Inj Sci 2019; 9(1): 36-42.
[http://dx.doi.org/10.4103/IJCIIS.IJCIIS_40_18] [PMID: 30989067]
[22] Su S, Wong G, Shi W, et al. Epidemiology, genetic recombination, and pathogenesis of coronaviruses. Trends Microbiol 2016; 24(6): 490-502.
[http://dx.doi.org/10.1016/j.tim.2016.03.003] [PMID: 27012512]
[23] Zhao Z, Li H, Wu X, et al. Moderate mutation rate in the SARS coronavirus genome and its implications. BMC Evol Biol 2004; 4: 21.
[http://dx.doi.org/10.1186/1471-2148-4-21] [PMID: 15222897]
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Debomoy K. Lahiri
(Indiana University School of Medicine, USA)

"Open access journals represent a major break-through in publishing. They provide easy access to the latest research on a wide variety of issues. Relevant and timely articles are made available in a fraction of the time taken by more conventional publishers. Articles are of uniformly high quality and written by the world's leading authorities."


Robert Looney
(Naval Postgraduate School, USA)

"Open access journals have transformed the way scientific data is published and disseminated: particularly, whilst ensuring a high quality standard and transparency in the editorial process, they have increased the access to the scientific literature by those researchers that have limited library support or that are working on small budgets."


Richard Reithinger
(Westat, USA)

"Not only do open access journals greatly improve the access to high quality information for scientists in the developing world, it also provides extra exposure for our papers."


J. Ferwerda
(University of Oxford, UK)

"Open Access 'Chemistry' Journals allow the dissemination of knowledge at your finger tips without paying for the scientific content."


Sean L. Kitson
(Almac Sciences, Northern Ireland)

"In principle, all scientific journals should have open access, as should be science itself. Open access journals are very helpful for students, researchers and the general public including people from institutions which do not have library or cannot afford to subscribe scientific journals. The articles are high standard and cover a wide area."


Hubert Wolterbeek
(Delft University of Technology, The Netherlands)

"The widest possible diffusion of information is critical for the advancement of science. In this perspective, open access journals are instrumental in fostering researches and achievements."


Alessandro Laviano
(Sapienza - University of Rome, Italy)

"Open access journals are very useful for all scientists as they can have quick information in the different fields of science."


Philippe Hernigou
(Paris University, France)

"There are many scientists who can not afford the rather expensive subscriptions to scientific journals. Open access journals offer a good alternative for free access to good quality scientific information."


Fidel Toldrá
(Instituto de Agroquimica y Tecnologia de Alimentos, Spain)

"Open access journals have become a fundamental tool for students, researchers, patients and the general public. Many people from institutions which do not have library or cannot afford to subscribe scientific journals benefit of them on a daily basis. The articles are among the best and cover most scientific areas."


M. Bendandi
(University Clinic of Navarre, Spain)

"These journals provide researchers with a platform for rapid, open access scientific communication. The articles are of high quality and broad scope."


Peter Chiba
(University of Vienna, Austria)

"Open access journals are probably one of the most important contributions to promote and diffuse science worldwide."


Jaime Sampaio
(University of Trás-os-Montes e Alto Douro, Portugal)

"Open access journals make up a new and rather revolutionary way to scientific publication. This option opens several quite interesting possibilities to disseminate openly and freely new knowledge and even to facilitate interpersonal communication among scientists."


Eduardo A. Castro
(INIFTA, Argentina)

"Open access journals are freely available online throughout the world, for you to read, download, copy, distribute, and use. The articles published in the open access journals are high quality and cover a wide range of fields."


Kenji Hashimoto
(Chiba University, Japan)

"Open Access journals offer an innovative and efficient way of publication for academics and professionals in a wide range of disciplines. The papers published are of high quality after rigorous peer review and they are Indexed in: major international databases. I read Open Access journals to keep abreast of the recent development in my field of study."


Daniel Shek
(Chinese University of Hong Kong, Hong Kong)

"It is a modern trend for publishers to establish open access journals. Researchers, faculty members, and students will be greatly benefited by the new journals of Bentham Science Publishers Ltd. in this category."


Jih Ru Hwu
(National Central University, Taiwan)


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