Introduction
Coronaviruses (CoVs) belong to the subfamily Othocoronavirinae, in the family Coronaviridae of the order Nidovirales. According to the 10th Report on Virus Taxonomy from the International Committee on Taxonomy of Viruses (ICTV), the Othocoronavirinae is comprised of four genera, including alphacoronavirus (alpha-CoV), betacoronavirus (beta-CoV), gammacoronavirus (gamma-CoV), and deltacoronavirus (delta-CoV) (King et al., 2018). Alpha- and beta-CoVs can infect mammals, including but not limited to bats, pigs, cats, mice, and humans (Kusanagi et al., 1992; Li et al., 2005b; Poon et al., 2005; Drexler et al., 2014; Pedersen, 2014; Kudelova et al., 2015; Cui et al., 2019). Gamma- and delta-CoVs usually infect birds, while some of them could infect mammals (Woo et al., 2009a, 2012, 2014; Ma et al., 2015). Since the late sixties, CoVs have been recognized as one of the viral sources responsible for the common cold. Among all CoVs identified so far, seven have the ability to infect humans, including human coronavirus 229E (HCoV-229E) and human coronavirus NL63 (HCoV-NL63), which belong to alpha-CoVs (Hamre and Procknow, 1966; Chiu et al., 2005), as well as human coronavirus OC43 (HCoV-OC43), human coronavirus HKU1 (HCoV-HKU1), severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and the newly emerged coronavirus (2019-nCoV), which are known to be beta-CoVs (Drosten et al., 2003; Ksiazek et al., 2003; Vabret et al., 2003; Woo et al., 2005; Zaki et al., 2012; Du et al., 2016b; Zhang et al., 2020; Zhu et al., 2020) (Figure 1).
FIGURE 1  Phylogenetic tree of coronaviruses (CoVs) based on the nucleotide sequences of RNA dependent RNA polymerase (RdRp). The Tree, with 1,000 bootstrap values, was constructed by the maximum likelihood method using MEGA 6. The four main phylogenetic clusters correspond to genera alpha-CoV, beta-CoV, gamma-CoV, and delta-CoV. Each CoV genus contains different subgenera. The letters in blue indicate human CoVs. Four human CoVs, including HCoV-229E, HCoV-NL63, HCoV-OC43, and HCoV-HKU1, have been identified in humans, but without causing severe infections. HCoV-229E was isolated from nasal secretions of medical students with minor upper respiratory disease. This virus was an original isolate, and was first reported in the 1960s (Hamre and Procknow, 1966). In addition to HCoV-229E, several studies have reported the recovery of HCoV-OC43 from patients with upper respiratory tract illness (Tyrrell and Bynoe, 1965; Hamre et al., 1967; McIntosh et al., 1967; Kapikian et al., 1969). In 2004, HCoV-NL63 was isolated from clinical species of infants suffering from pneumonia or bronchiolitis, and characterized for its ability to infect human respiratory tract (Fouchier et al., 2004; van der Hoek et al., 2004). The subsequent study in 2005 identified a new member of CoVs, named HCoV-HKU1, from a 71-year-old man with pneumonia (Woo et al., 2005). Generally, these four viruses are the most common pathogens causing mild upper respiratory infection or asymptomatic infection, and count for about 30% of all colds (Myint, 1994; Lau et al., 2006; Kim et al., 2017). In the serological surveillance on healthy adults, HCoV-229E, HCoV-NL63, and HCoV-OC43 demonstrated more than 90% seropositive with the immunological assay. It appears common for these CoVs to infect children (Mourez et al., 2007; Shao et al., 2007; Severance et al., 2008). In contrast to the above three human CoVs, HCoV-HKU1 has around 50% seropositive in healthy individuals and a relatively low exposure rate in children (Lehmann et al., 2008; Severance et al., 2008). Although the prevalence of various CoVs is different, the incidence among these viruses shows no significant difference (Woo et al., 2009b). The afore-mentioned four CoVs have been detected in 2.1–17.9% of clinical specimens (Esper et al., 2006; Lau et al., 2006; Gerna et al., 2007; Regamey et al., 2008; Matoba et al., 2015; Killerby et al., 2018). These viruses have also been associated with lower respiratory tract illness in children, elders, and immunodeficient individuals (Falsey et al., 2002; Fouchier et al., 2004; Woo et al., 2005; Gerna et al., 2006). HCoV-229E and HCoV-OC43 may lead to central nervous system infection since viral RNAs are detected in the brain of some patients (Arbour et al., 2000; Desforges et al., 2014).
Unlike the above four human CoVs, SARS-CoV, MERS-CoV, and 2019-nCoV have caused severe pneumonia and/or failure of other organs, even death, among infected populations (Nicholls et al., 2003; Zhong et al., 2003; Zaki et al., 2012; Zhu et al., 2020). The epidemic outbreak of SARS-CoV began in the Guangdong Province of China in November 2002, and spread through human-to-human transmission to other parts of the world within a few months (Ksiazek et al., 2003). From November 2002 to August 2003, SARS-CoV infected more than 8,098 people in 29 counties, resulting in over 774 deaths with ∼10% fatality rate (Du et al., 2009a). Palm civets serving as a potential intermediate host of this virus were traced immediately (Tu et al., 2004). Chinese horseshoe bats (Rhinolophus sinicus) are the natural reservoir of SARS-CoV (Li et al., 2005b). Various bat SARS-related CoVs (SARSr-CoV) have been identified in Yunnan, China, several of which can infect human cells, and have been further characterized (Ge et al., 2013; Hu et al., 2017). These discoveries indicate the threat of re-emergence of SARS-CoV or SARSr-CoV.
A decade later, another highly pathogenic human CoV, MERS-CoV, emerged, and the first patient with MERS-CoV infection was reported in Saudi Arabia in June 2012 (Zaki et al., 2012). By December 26, 2019, a total of 2,494 laboratory-confirmed cases of MERS, including 858 associated deaths in 27 countries (fatality rate 34.4%), were reported to the WHO1. Globally, the majority (about 80%) of human cases have been reported in Saudi Arabia, where people get infected through direct contact with infected dromedary camels or persons2 (Zaki et al., 2012). Isolation of MERS-CoV and detection of neutralizing antibodies from dromedary camels suggest that these camels are potentially an important intermediate host (Reusken et al., 2013; Azhar et al., 2014). Similar to SARS-CoV, MERS-CoV is also an emerging zoonotic virus (Li and Du, 2019). Bats habituate several CoVs phylogenetically related to MERS-CoV, and some of them are identical to MERS-CoVs, suggesting that MERS-CoV may originate from bats (Annan et al., 2013; Lelli et al., 2013; Lau et al., 2018; Luo et al., 2018a). Different from SARS-CoV, which has not caused infections in humans since 2004 (Du et al., 2009a), the transmission of MERS-CoV has not been interrupted, and the infected human cases continue increasing1 (Mobaraki and Ahmadzadeh, 2019). Currently, human-to-human transmission of MERS-CoV is limited.
A new CoV, 2019-nCoV, has caught worldwide attention (Liu and Saif, 2020; Zhang et al., 2020). It was first identified in Wuhan, China in December 2019, from patients with pneumonia (Zhu et al., 2020), and has infected more than 70000 people globally, including 2,009 deaths (∼2.7% fatality rate), as of February 19, 2020, particularly in China, and the other parts of the world, including Australia, Japan, Malaysia, Singapore, South Korea, Viet Nam, Cambodia, Philippines, Thailand, Nepal, Sri Lanka, India, United States, Canada, France, Finland, Germany, Italy, Russian Federation, Spain, Sweden, United Kingdom, Belgium, Egypt, and United Arab Emirates3. Different from MERS-CoV but similar to SARS-CoV, 2019-nCoV can cause human-to-human transmission, and its intermediate host that leads to the current human infection and outbreak is still under investigation.