1. Introduction
In late December 2019, a viral outbreak of unknown etiology in Wuhan, China was reported in which several patients were admitted to hospitals with a diagnoses of pneumonia and respiratory distress (Bogoch et al., 2020). This “viral pneumonia” was found to be linked to the Huanan Seafood Market in Wuhan, China (Huang et al., 2020). This emerging novel coronavirus (nCoV), was named SARS-CoV-2, and on February 11, 2020 the WHO named the disease associated with SARS-CoV-2 Corona virus disease 19 (COVID-19) (Q. Li et al., 2020; Rothan & Byrareddy, 2020). Similar to previously detected HCoVs, such as SARS-CoV and MERS-CoV, this virus is known to infect people and spread rapidly from person-to-person through droplets (Lewis, 2020). The COVID-19 outbreak was recognized as a pandemic on March 11, 2020 (Cucinotta & Vanelli, 2020). As of May 29, 2020, the virus has surpassed 5,888,498 infections and 363,210 deaths worldwide. At the same time, in the United States of America there are 1,743,235 confirmed cases and 102,516 deaths. (https://coronavirus.jhu.edu/us-map)
CoVs are enveloped and positive-stranded RNA viruses that have large viral genomes ranging from 26- 32 kb in length (Denison, Graham, Donaldson, Eckerle, & Baric, 2011). Common HCoVs such as 229E and NL63 belong to alpha coronavirus genus, while comparatively OC43 and HKU1 belong to the genus betacoronavirus, which can cause mild and self-limiting respiratory tract infections (Corman, Muth, Niemeyer, & Drosten, 2018). In the last two decades, the pandemics associated with SARS-CoV and MERS-CoV, betacoronaviruses, cause Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS) respectively (11,12). The antigenicity of the virus depends on the enveloped spike protein, which is the major determinant of attachment and entry of the virus into host cells (Sui et al., 2004). The viruses belonging to the family Coronaviridae have a wide variety of hosts including: birds, pigs, cats, dogs, bats, pangolins, and humans (Woo et al., 2012). These beta coronaviruses have resulted in symptoms of varying severity ranging from comparative symptoms of common cold affecting the upper respiratory tract (URT), to more severe symptoms of bronchitis, pneumonia, and associated fatalities affecting the lower respiratory tract (LRT) (Peiris et al., 2003; Raj, Osterhaus, Fouchier, & Haagmans, 2014). The outbreak of SARS pandemic in 2002 resulted in a 9.6 % fatality rate from 8096 cases and almost 774 fatalities worldwide. (”World Health Organization . Geneva (Switzerland): World Health Organization; 2003. Summary of probable SARS cases with onset of illness from 1 November 2002 to 31 July 2003 ”). MERS which emerged in 2012 and observed for new cases until October 2018, had 2229 confirmed cases and 791 deaths for a higher rate of fatality near 35.5% (”World Health Organization . Geneva (Switzerland): World Health Organization; 2019. MERS situation update, December 2019,”). These viruses are known for being cross-species (zoonotic) and human-to-human communicable from where transmission can be coupled with severe pathological effects (Corman et al., 2018). SARS-CoV and MERS-CoV use Angiotensin-Converting Enzyme 2 (ACE2) (W. Li et al., 2003) and Dipeptidyl peptidase 4 (DPP-4) (Raj et al., 2013) as receptors to enter host cells, respectively.
SARS-CoV-2 belongs to the same clade of beta coronaviruses as SARS-CoV and MERS-CoV, with more than 80% and 50% sequence similarity, respectively (Cui, Li, & Shi, 2019). The genome of SARS-CoV-2, which was isolated from a cluster of patients with pneumonia in Wuhan, had more than 90% nucleotide identity with the bat CoV, RaTG13 (Zhou et al., 2020). The exact route of animal-to-human transmission of SARS-CoV-2 is still unclear but genomic data suggest their evolution is from bats to humans (Zhou et al., 2020) (Figure 1 ). Recent study suggested that 99% sequence similarity of SARS-CoV-2 structural proteins with coronavirus isolated from pangolins suggesting pangolins as intermediate hosts (Xiao et al., 2020) (Figure 1 ). Another study suggested that snakes could be an intermediate host for SARS-CoV-2 based on codon usage (Ji, Wang, Zhao, Zai, & Li, 2020) (Figure 1 ). In contrast, the bamboo rat has also been proposed to be the intermediate host (Nanshan, 2020) (Figure 1 ). Despite active investigation, the definitive animal reservoir responsible for cross-species transmission of SARS-CoV-2 from animals to humans remains elusive (Bassetti, Vena, & Giacobbe, 2020). Like SARS and MERS, clinical symptoms of COVID-19 range from acute to severe. Characteristic mild symptoms include fever, sore throat with a dry cough, respiratory stress, and myalgia (Huang et al., 2020). In severe conditions, bilateral lung ground-glass opacity is observed under chest-computed tomography. (Acharya, Kevadiya, Gendelman, & Byrareddy, 2020; H. Shi et al., 2020). Neurological manifestations like dizziness, headache, ataxia, seizure with taste, smell and visual impairment were reported (Mao et al., 2020) Histopathological reports showed diffuse alveolar damage and pulmonary edema, indicating acute respiratory distress syndrome (Rothan & Byrareddy, 2020; Xu et al., 2020), which was also seen in SARS-CoV infection (Nicholls et al., 2003).
SARS-CoV-2 uses ACE2 as a receptor for binding and entering host cells, which is facilitated by the host protease Transmembrane Serine Protease 2 (TMPRSS2) (Hoffmann et al., 2020). ACE2 is expressed in airway epithelial cells, lung parenchyma, and vascular endothelial cells in the kidney and small intestine (Hamming et al., 2004). Therapeutic interventions for COVID-19 such as vaccines, antivirals, antibodies, etc are an active area of investigation (Mukherjee, 2020) and several are already in clinical trials (Scavone et al., 2020). In-vitro cell models and organoids are also helpful to understand the virus entry, life cycle and testing the efficacy of therapeutics (Takayama, 2020) but they are unable to exhibit the exact pathological changes and lesions that are specific to particular organs. Therefore, suitable biological relevant animal models are necessary for testing the safety and efficacy of the vaccines, antivirals and other potential therapeutics that are currently in the pipeline.