History

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novel SARS-CoV and MERS-CoV. There is strong evidence that these viruses emerged recently from animal reservoirs, originating in bats and transmitted to man via intermediate host species. Intra- and inter-species transmission of CoVs, and genetic recombination events contribute to the emergence of new CoV strains. The following sections will review CoV in general with a more detailed appraisal of the origin, evolution, virological structure and pathogenesis of SARS-CoV-2 to expand knowledge pertaining to COVID-19 and prospective anti-viral and vaccine therapies.

Coronavirus disease was first described as early as 1930 presenting as infectious bronchitis in chickens, gastroenteritis in pigs and severe hepatitis and neurological disease in mice. The first coronavirus to be isolated was the Infectious bronchitis virus (IBV) from chickens with respiratory disease reported by Beaudette and Hudson in 1937 (Zuckerman 2009, Korsman 2012, Knipe 2013). The first human coronaviruses were discovered much later. In 1965, Tyrrell and Bynoe isolated a virus, which they designated B814, from a respiratory tract sample of a boy with a common cold by passage in embryonic tracheal organ cultures (Zuckerman 2009). At the same time, Hamre and Procknow were able to grow a virus, designated 229E, in tissue culture from samples obtained from medical students with upper respiratory tract infections. These two viruses were both ether-sensitive, shared identical morphology under electron microscope, and were not related to any known human viruses. Furthermore, B814 resembled avian IBV suggesting a similar origin (Perlman 2020, Kahn 2005). Following similar techniques of tissue culture, English scientist McIntosh and colleagues recovered multiple isolates of previously unknown pathogenic agents from human respiratory tract samples. The human viral prototype was designated OC43 indicating it was grown in organ culture (Perlman 2020, Kahn 2005). OC43 morphologically resembled two animal CoV, mouse hepatitis virus and transmissible gastroenteritis virus of swine. The unique feature were the distinct protruding spike proteins present on the viral surface reminiscent of a crown. This group of unrecognized viruses was thus named “Coronaviridae” which received and accepted by the International Committee for the Taxonomy of Viruses (ICTV) in 1968,. (Perlman 2020, Kahn 2005, Almeida 1968). In November of 2002 an unusual and lethal form of pneumonia, termed severe acute respiratory syndrome (SARS), emerged in Guangdong province, Peo-

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ple’s Republic of China (Berger 2004). A novel coronavirus, SARS-CoV, was isolated and identified in April 2003 (Kuiken 2003) as the causative agent. SARS spread to Hong Kong and then internationally leading to a global epidemic. Transmission was presumably zoonotic entering the human population from an uncertain animal source. Studies suggest that SARS originated from Rhinolophid bats with traded civets as an intermediatry host. Direct transmission is improbable as SARS-CoV was not found in farmed or wildcaught civets (Hu B 2015). By July 2003, the epidemic had come to an end due to intense public health response and infection control policies. A total of 8096 cases have been recorded to date,744 of them fatal, with a resulting in a case fatality rate of 9.6% (Perlman 2020, Korsman 2012, Kahn 2005).

The impact of SARS instigated a notable surge of research interest in CoV. This resulted in the discovery of numerous emerging human and animal CoV, the development of sensitive molecular methods for detection and characterisation, and improved understanding of viral pathogenesis. These discoveries included an additional two endemic human CoV, NL63 and HKU-1 (Perlman 2020, Kahn 2005). In 2004, van der Hoek and colleagues isolated HCoV-NL63 from infants and children with respiratory disease in Netherlands and New Haven, Connecticut (van der Hoek 2004). Phylogenetic analysis demonstrated that this virus was a CoV related to HCoV-229E. The following year (2005), HCoV-HKU-1 was isolated from an adult in Hong Kong after he presented with respiratory disease following a trip to Shen-zhen, China, a previously SARS-endemic area, Sequencing showed that HKU-1 was genetically distinct from any known HCoV and was indeed a novel coronavirus (Woo P 2005). Human CoV 229E, OC43, NL-63 and HKU-1 have existed for decades or longer and are endemic in the human population. They are the cause of a substantial proportion of “flulike” illness in infants and children. Introduction into humans is zoonotic in origin with bats identified as the most probable ancestoral host (Corman 2015, Huyhn 2012 ). In June 2012, yet another novel CoV was isolated from the sputum sample of a Saudi Arabian man with severe pneumonia. This novel CoV was termed Middle East Respiratory Syndrome (MERS), reflecting the geographical area affected. To date, sporadic zoonotic cases of MERS continue to occur, with occasional onward transmission from human to human mostly under conditions of insufficient infection control measures. To date there are 2519 cases and 866 deaths recorded, with a resultant case fatality rate of 37.1% (Perlman 2020). The SARS, MERS and most recent SARS-CoV-2 epidemics are reminders