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Only two HCoVs, i.e., HCoV-229E and HCoV-OC43, had complete ge-nome sequences available before 2003, and both were identified in the mid-1960s(Hamre et al., 1967; McIntosh et al., 1967). SARS-CoV was identified in March 2003 during the SARS epidemic. The HCoVs NL63 and HKU1, which were distributed globally, were identified in 2004 and 2005, respectively. Howe-ver, other studies have suggested that HCoV-NL63 had already existed in humans(Pyrc et al., 2006). Similarly, some studies have shown that HCoV-HKU1 strains have been present in the human population for some time(Gerna et al., 2006).
HCoV-229E and HCoV-NL63 belong to the genus Alphacoronavirus, whereas HCoV-OC43 and HCoV-HKU1 belong to lineage A Betaco-ronavirus. These four viruses are responsible for mild upper-respiratory tract infections, causing more severe respiratory pathologies in immunocompromised patients, elderly peo-ple, and infants(Fouchier et al., 2004). SARS-CoV and MERS-CoV belong to lineage B and C Betaco-ronaviruses, respectively, and both induce more severe lower respiratory infections and fatality.
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SARS is the first transmissible p and emic disease of previously unknown etiology identified in the 21st century. In November 2002, an unusual atypical pneumonia caused by SARS-CoV first occurred in Foshan City Guangdong Province, China(Cheng et al., 2007), and the virus was first isolated from an open lung biopsy of a 65-year-old doctor who traveled to Hong Kong from Guangzhou. Subsequently, the infection spread to more than 30 different countries, including North America, Europe, South America, and Southeast Asia, resulting in a global outbreak with 8096 cases and 774 deaths. The fatality rate was nearly 10% in 2002-2003, having substantial economic effects(Drosten et al., 2003). Investigation of live-animal markets in China indicated that the animal-to-human interface provided a mechanism for SARS-CoV to adapt to human-to-human transmission. SARS has been recognized as a global threat; although the outbreak of SARS was halted in 2004 through epidemiological measures, recent identification of bat SARS-like CoVs that can recognize human angiotensin 1-converting enzyme 2(ACE2)receptors and replicate efficiently in primate cells indicates the inevitability of a SARS-CoV-like virus reemergence event in the near future(Guan et al., 2003).
Ten years later, MERS emerged in 2012 is still circulating in many Mi-ddle East countries. MERS-CoV was first isolated from the sputum of a 60-year-old man who presented with acute pneumonia and subsequent renal failure with a fatal outcome in Saudi Arabia in 2012(Zaki et al., 2012). The median incubation period of MERS-CoV(about 5-14 days)is longer than that of SARA-CoV(about 4-7 days). Although travel-associated MERS cases have been reported in 26 countries outside the Middle East(including Germany, Italy, France, Tunisia, and the United Kingdom), most cases of MERS-CoV infection have occurred in the Middle East(i.e., Saudi Arabia, Jordan, Qatar, and the United Arab Emirates). As of October 30, 2015, 1618 cases of laboratory-confirmed MERS-CoV infection have been reported; of these, 579 died. Many patients with MERS develop acute renal failure. The fatality rate of MERS-CoV(up to 40%)seems higher than that of SARS-CoV(nearly 10%). Wide human-to-human spread of MERS-CoV is not efficient; however, outbreaks have been reported to occur in hospitals and travelers returning from the Middle East(Zaki et al., 2012).
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HCoV-229E and HCoV-OC43 were the first HCoVs to be identified, accounting for 15%-30% of common colds and rarely causing severe symptoms(Holmes, 2003). HCoV-229E is associated with numerous respiratory diseases, ranging from mild cold to severe pneumonia in immunocompromised patients(Pene et al., 2003; Boucher et al., 2007). Young patients approximately 3-years old and younger may be more susceptible to infection with this virus. In addition, a recent study showed that HCoV-229E shares vital traits with MERS-CoV and is linked with CoVs identified in bats as well(Corman et al., 2015).
HCoV-OC43 was firstly obtained from a patient with a cold and subsequently inoculated in human embryonic trachea organ culture(OC)in 1967(McIntosh et al., 1967). Virologists rarely studied this virus until SARS-CoV appeared in 2003. However, HCoV-OC43 has now been shown to occur frequently thr-oughout the world and often results in acute respiratory tract infections(Lau et al., 2006), particularly lower respiratory tract infections with co-infection by other respiratory viruses(Jean et al., 2013). Immunocompromised patients, elderly patients, and infants may be high risk populations for infection by this virus. Moreover, some studies have shown that HCoV-OC43 may cause gastrointestinal and central nervous system diseases as well(Esper et al., 2010).
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HCoV-NL63 was first isolated from a 7-year-old child hospitalized with chest radiographic evidence of bronchiolitis in the Netherl and s in 2003(Pyrc et al., 2007). HCoV-NL63 had been circulating in the human population from before 1988(Fouchier et al., 2004). Most cases occur during early summer and autumn in tropical and subtropical areas(Wu et al., 2008; Pyrc et al., 2007), and during winter in Euro-pean countries. Additionally, co-infection with other respiratory viruses may occur(Gaunt et al., 2010). HCoV-NL63 is a significant pathogen that contributes to the hospitalization of children, with an estimated 224 hospital admissions per 100, 000 individuals ages 6 years and younger each year in Hong Kong(Chiu et al., 2005).
In 2004, HCoV-HKU1 was first reported in a 71-year-old man with community-acquired pneumonia in Hong Kong(Woo et al., 2005), and was then found worldwide shortly thereafter. Both the elderly with underlying illnesses and young children are more susceptible to infection by this virus(Lau et al., 2006). In addition to community-acquired pneumonia, HCoV-HKU1 can also lead to asthmatic exacerbation and acute bronchiolitis. Febrile seizure is the most common symptom in HCoV-HKU1 infection(Lau et al., 2006). HCoV-HKU1 was also found in a patient with meningitis(Gaunt et al., 2010). The peak seasons for this virus are winter and spring, similar to those for influenza(Lee et al., 2013; Gerna et al., 2007). Both viruses have circulated globally, causing many diseases in the human population.
The four circulating HCoVs, i.e., HCoV-229E, HCoV-NL63, HCoV-OC43, and HCoV-HKU1, can likely be classified as common cold viruses but also may cause severe lower respiratory tract infections in patients with underlying diseases, young children, and the elderly. HCoV-OC43 and HCoV-NL63 may elicit immunity that protects from subsequent HCoV-HKU1 and HCoV-229E infection, respectively, which would explain why HCoV-OC43 and HCoV-NL63 are the most frequently identified HCoVs(Dijkman et al., 2012). HCoV-NL63 and HCoV-OC43 infections occur frequently in early childhood and are more common than HCoV-HKU1 or HCoV-229E infections. In addition, Turgay found HCoV-229E and HCoV-OC43 co-infection in pediatric cases with lower respiratory tract infection and acute flaccid paralysis(AFP)for the first time(Turgay et al., 2015)(Table 1).
Name YearDiscovered Possible Hosts ViralRecepotor Emerging/PreviouslyCirculatin FatalityRate CurrentCirculation HCoV-229E 1966 Hipposiderid bats ACE2 Previously Circulating low Yes HCoV-OC43 1967 Mouse/Bovine Unknown Previously Circulating low Yes SARS-CoV 2003 Horseshoe bats ACE2 Emerging ~10% No HCoV-NL63 2003 Bat unknown ACE2 Previously Circulating low Yes HCoV-HUK1 2004 Bat unkown Unknown Previously Circulating low Yes MERS-HCoV 2012 Taphozous perforatus bat DDP4 Emerging ~40% Yes Table 1. Six identified human coronaviruses.