Coronaviruses and Recent Outbreaks
First discovered in the 1960s, CoVs are part of the Coronaviridae family of enveloped positive single-strand RNA viruses (13, 14). The subfamily Orthocoronaviridae includes four genera: alphacoronavirus, betacoronavirus, gammacoronavirus, and deltacoronavirus (15). Alpha- and betacoronaviruses circulate in mammals, including bats, gammacoronaviruses infect mostly avian species, and deltacoronaviruses infect birds and mammals (15). Low pathogenic human CoVs (hCoVs), such as HCoV-299E (16), infect upper airways and etiological studies suggest they account for 15–30% of common colds (17, 18). On the other hand, highly pathogenic CoVs infect the lower respiratory tract and can cause severe pneumonia (19). These highly pathogenic CoVs include SARS-CoV-1, the virus responsible for the 2002–2004 Severe Acute Respiratory Syndrome (SARS) epidemic, and MERS-CoV, the virus responsible for the outbreak of Middle Eastern Respiratory Syndrome (MERS) in 2015 (19–21). While highly pathogenic CoVs have become a relatively recent issue for humans; feline, canine, and bovine CoVs have long been recognized as significant pathogens with implications in veterinary medicine and agriculture (22, 23). All CoVs have a roughly 30 kb genome packed into an enveloped helical capsid ranging from 80 to 120 nm (24). At minimum, Coronaviridae members encode 4 structural and 16 non-structural proteins (14) with the family owing its name to the crown-like appearance produced by their spike (S) proteins (25). Mutations in the S protein have allowed SARS-CoV1/2 to co-opt ACE2 or MERS-CoV to co-opt dipeptidyl peptidase 4 (DPP4) receptor/CD26 as viral entry receptors, thus facilitating the zoonosis of non-human CoVs (15, 26–28). In addition, another mechanism that may have allowed these viruses to adapt to human hosts is through S protein cleavage by host cell proteases to expose the S2 domain fusion peptide, which induces viral and cellular membrane fusion and results in the release of viral genome into the cytoplasm (15). Genetic sequencing revealed SARS-CoV-2 to be a betacoronavirus that shares 79.0% nucleotide identity with SARS-CoV-1 and 51.8% identity to MERS-CoV (29).
The epidemic of SARS in 2002–2004 caused by SARS-CoV-1 illustrated the devastating potential of coronaviruses to cause serious disease in humans (24). SARS ultimately reached 29 countries and 5 continents causing over 8,000 infections and over 900 deaths. The basic reproductive rate (R0) or the number of expected cases arising from one infected individual, ranges from 2 to 4 (20, 30, 31). With its reservoir in bats, SARS-CoV-1 is a zoonosis that was transmitted to humans by palm civets (24, 32, 33). SARS-CoV-1 infects lung pneumocytes (34) and enterocytes in the digestive tract (35) most often producing flu-like symptoms (36, 37). More severe presentations including pneumonia, pronounced lymphopenia, liver abnormalities, and acute respiratory distress syndrome (ARDS) were also reported, with most fatalities due to respiratory failure (19, 36–39).
The subsequent MERS-CoV outbreak in 2015 also originated in bats, with dromedary camels being the intermediary host (14, 40, 41). The R0 for MERS-CoV is estimated to be under 1 (21). The extent of MERS-CoV transmission was more limited than SARS-CoV-1, but its case fatality rate was greater with 2,494 cases over 27 countries and 858 deaths being reported at the end of 2019 (21). Common presentations for MERS-CoV include fever, dyspnea, muscle pain, and digestive tract symptoms and disease progression is more likely in those with comorbidities (42).
Like SARS-CoV-1 and MERS-CoV, SARS-CoV-2 is thought to have originated in bats through an unknown intermediary host (43). At the time of writing, the number of global infections is estimated to be over 5,000,000 with over 340,000 deaths (44) and the R0 is roughly 2.2 (45). Like other diseases caused by infectious CoVs, most patients present with flu-like symptoms including fever, cough, and lethargy, with the development of pneumonia and ARDS often proving fatal (46). Furthermore, patients with underlying conditions are at risk for further complications if infected with COVID-19, such as those with cardiovascular disease (47). SARS-CoV-2 has been posthumously detected in not only the lungs, but the pharynx, heart, liver, brain, and kidneys (48). Transmission of SARS-CoV-2 is thought to mainly occur through direct contact/inhalation of respiratory droplets and aerosols from infected carriers, but indirect transmission by fomites has also been reported, although less efficient (49, 50). SARS-CoV-2 viral entrance is thought to be mediated by binding of the S protein to the ACE2 receptor (51, 52), although this is still under debate (53). While direct cytopathic effects are thought to play a major role in CoV pathology, studies have suggested that a dysregulated immune response resulting in pathological inflammation is also partly responsible (19). With the current pandemic already surpassing the previous CoV outbreaks (54), rapid deployment of novel approaches to understanding and treating coronavirus infections are needed.