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Review Article| Volume 29, ISSUE 4, P715-724, December 2009

Recently Discovered Human Coronaviruses

DOI:https://doi.org/10.1016/j.cll.2009.07.007
Recently Discovered Human Coronaviruses
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      Keywords

      Coronaviruses (CoVs) are a large and diverse group of positive-stranded RNA viruses in the Coronaviridae family, which also comprises members of the Torovirus genera.
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      Together with the Arteriviridae and Roniviridae families, Coronaviridae are grouped in the order of Nidovirales, based on their conserved genome organization and mechanism of replication.
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      A contemporary view of coronavirus transcription.
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      Coronavirus particles are enveloped and measure 120 to 160 nm in diameter, containing a linear, single and positive stranded RNA genome with an average length of 27 to 31 kb, the largest RNA genome described so far.
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      The viral RNA molecule is organized together with multiple copies of the nucleocapsid (N) protein to form a flexible core inside the viral membrane that constitutes the spike (S), envelope (E), and membrane (M) proteins. In certain isolates, an additional structural protein is present on the virion: hemagglutinin esterase (HE). The heavily glycosylated S proteins are crucial for CoVs to establish and maintain an infection cycle, by interacting with specific cellular entry molecules to initiate a fusion between viral and cellular membranes.
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      In the 1930s, isolation of the first CoV, avian bronchitis virus (IBV), was reported.
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      Ever since, many CoVs have been discovered in a broad range of hosts, including mammals and birds. CoVs are transmitted by means of respiratory aerosols and the fecal–oral route of infection, and primarily target mucosal surfaces of respiratory and intestinal tracts, causing illnesses of varying severity. In addition, manifestations of neurologic, hepatic, and systemic disorders are induced after infection with certain CoVs.
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      Human CoV (HCoV) infections initially seemed to be associated primarily with mild and self-limiting upper respiratory tract infections, such as the common cold, and were not thought to be connected to severe human illnesses.
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      Antivir Ther. 2007; 12: 651-658
      Coronaviral pathogens, however, gained renewed scientific interest in 2003, when a novel HCoV was proven to be the etiologic agent of the worldwide severe acute respiratory syndrome (SARS) epidemic.
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      Soon thereafter, numerous new CoVs were discovered, including two species with the potential to infect humans: HCoV-NL63 and HCoV-HKU1.
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      • Hartwig N.G.
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      A previously undescribed coronavirus associated with respiratory disease in humans.
      Proc Natl Acad Sci U S A. 2004; 101: 6212-6216
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      • et al.
      Identification of a new human coronavirus.
      Nat Med. 2004; 10: 368-373
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      • et al.
      Characterization and complete genome sequence of a novel coronavirus, coronavirus HKU1, from patients with pneumonia.
      J Virol. 2005; 79: 884-895

      Human coronavirus 229E and human coronavirus OC43: common cold agents

      For a long time, only two HCoV species were known: HCoV-229E and HCoV-OC43, both isolated in the mid-1960s. HCoV-229E was recovered from medical students in Chicago who had clinical symptoms of upper respiratory tract infection. The virus could be propagated on primary human kidney cells and human embryonic lung cells.
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      Shortly thereafter, a distinct CoV was isolated using human embryonic tracheal organ cultures, and termed OC43 for organ culture number 43.
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      Inoculation of volunteers at the Common Cold Unit in Salisbury, United Kingdom, demonstrated a causal relationship between HCoV-229E and HCoV-OC43 infections and common cold symptoms.
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      The common cold is a typical self-limiting upper respiratory tract disease, characterized by mild clinical symptoms, including nasal obstruction and rhinorrhea, sneezing, sore throat, and cough. There is no single cause for this heterogeneous group of upper respiratory tract illnesses; in fact numerous viruses from several different families function as etiologic agents.
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      The common cold.
      Lancet. 2003; 361: 51-59
      Although rhinoviruses account for the largest proportion of all upper respiratory tract infections, HCoV-229E and HCoV-OC43 now are known to be responsible for a high number of these cases, which occur mainly during winter and early spring seasons in temperate climate countries.
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      Although coryza occurs more often during HCoV-229E infections, there are indications that sore throat manifestations are observed more frequently in patients who have HCoV-OC43 infections.
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      The behaviour of recent isolates of human respiratory coronavirus in vitro and in volunteers: evidence of heterogeneity among 229E-related strains.
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      Infants, elderly, and immunocompromised individuals are thought to be vulnerable for more severe upper and lower respiratory tract infections, including pneumonia, caused by infections with HCoV-229E and HCoV-OC43.
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      Human coronaviruses: what do they cause?.
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      Coronavirus infections of man associated with diseases other than the common cold.
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      Since their discovery, other pathologies have been connected occasionally to HCoV-OC43 and HCoV-229E. HCoV-OC43 initially was proposed to be involved in gastrointestinal (GI) disease development in children.
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      This hypothesis, however, never was confirmed by inoculation studies with healthy individuals.
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      Human coronaviruses: what do they cause?.
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      In addition, presence of CoV RNA in brain tissue and antibody concentrations in serum of multiple sclerosis (MS) patients, led to the suggestion of CoV involvement in MS etiology.
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      Although evidence for a significant correlation between presence of HCoV-229E and HCoV-OC43 RNA and MS has not been demonstrated,
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      accumulating recent data from cell culture and animal models indeed confirm their neurotropic and neuroinvasive potential.
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      Infection of primary cultures of human neural cells by human coronaviruses 229E and OC43.
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      Human coronavirus OC43 infection induces chronic encephalitis leading to disabilities in BALB/C mice.
      Virology. 2006; 349: 335-346
      Nevertheless, actual brain invasion in MS patients by HCoV-229E and HCoV-OC43 might be explained by a disrupted blood–brain barrier.
      • van der Hoek L.
      Human coronaviruses: what do they cause?.
      Antivir Ther. 2007; 12: 651-658

      Severe acute respiratory syndrome

      The first case of SARS, a severe lower respiratory tract illness with a mortality rate of 10%, emerged in November 2002 in Fushan City, China.
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      Subsequently, SARS spread rapidly throughout eastern Asia and to 28 other regions around the world, causing 774 deaths in 8098 infected individuals.
      Summary of probable SARS cases with onset of illness from November 1, 2002 to July 31, 2003.
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      In February 2003, a newly emerged HCoV, which originated from a wild animal reservoir, was demonstrated to be the etiologic agent of this syndrome.
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      Nature. 2003; 423: 240
      Of all HCoVs described thus far, SARS-CoV causes the most severe clinical symptoms. Of interest, SARS rarely is detected in young children, and if so, it seems to follow a less aggressive clinical course.
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      The strongest predictor of poor disease outcome appears to be an advanced age (older than 60 years).
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      By means of droplet inhalation, SARS-CoV reaches the respiratory tract and invades epithelial cells of trachea, bronchi, bronchioles, and alveoli.
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      Virus Res. 2008; 133: 4-12
      SARS-CoV typically causes a broad spectrum of disease, starting with an influenza-like syndrome, including symptoms such as high fever, malaise, rigors, and fatigue.
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      After disease onset, infections may progress to a nonsevere variant of disease or cough variant, characterized by relatively moderate symptoms.
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      Generally, 2 to 7 days after SARS onset, a typical respiratory phase is initiated, including nonproductive cough and dyspnea. In two thirds of infected patients, disease deteriorates toward an atypical pneumonia, with shortness of breath and poor alveolar oxygen exchange.
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      Symptoms may worsen even further into an acute respiratory distress syndrome (ARDS), as a result of progressive pulmonary immune infiltration, formation of hyaline membranes, diffuse alveolar damage (DAD), and a high viral burden.
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      Virus Res. 2008; 133: 4-12
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      JAMA. 2003; 290: 374-380
      ARDS is the most severe form of acute lung injury (ALI) and is regarded as the leading cause of death in SARS-CoV infected individuals.
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      Cell. 2008; 133: 235-249
      Lung injury in patients who have SARS is supposed to occur directly, by viral-mediated destruction of alveolar and bronchial epithelial cells, as well as indirectly, through extensive production of immune mediators.
      • Cameron M.J.
      • Bermejo-Martin J.F.
      • Danesh A.
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      Human immunopathogenesis of severe acute respiratory syndrome (SARS).
      Virus Res. 2008; 133: 13-19
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      Nat Rev Immunol. 2005; 5: 917-927

      Human coronavirus NL63 and human coronavirus HKU1 infections

      Shortly after the SARS-CoV outbreak, an unknown respiratory virus was isolated in Amsterdam, The Netherlands, in a nasopharyngeal aspirate specimen (sample NL63) from a 7-month-old infant suffering from coryza, bronchiolitis, conjunctivitis, and fever. The infectious agent was identified as a distinct and fourth human member of the Coronaviridae family: HCoV-NL63, using a novel technique to amplify viral genomes without a priori knowledge of their sequence.
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      • Pyrc K.
      • Jebbink M.F.
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      Identification of a new human coronavirus.
      Nat Med. 2004; 10: 368-373
      Within a few weeks, a second research group from The Netherlands reported detection of essentially the same virus, initially designated HCoV-NL.
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      • Hartwig N.G.
      • Bestebroer T.M.
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      A previously undescribed coronavirus associated with respiratory disease in humans.
      Proc Natl Acad Sci U S A. 2004; 101: 6212-6216
      Because similarity of these isolates is very high at the nucleotide level, they both represent the same species: HCoV-NL63. HCoV-NL63 is demonstrated to be genetically most closely related to HCoV-229E.
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      Mosaic structure of human coronavirus NL63, one thousand years of evolution.
      J Mol Biol. 2006; 364: 964-973
      HCoV-NL63 infections are recognized throughout the whole world, and are identified as nonfatal upper and lower respiratory tract infections in infants, the elderly, and immunocompromised adults.
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      Human coronaviruses: what do they cause?.
      Antivir Ther. 2007; 12: 651-658
      In addition, a clear association between HCoV-NL63 infections and trachea inflammation in children (laryngotracheitis or croup) has been demonstrated through population-based studies.
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      Croup is associated with the novel coronavirus NL63.
      PLoS Med. 2005; 2: 764-770
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      The association of newly identified respiratory viruses with lower respiratory tract infections in Korean children, 2000–2005.
      Clin Infect Dis. 2006; 43: 585-592
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      Human coronavirus-NL63 infections in Korean children, 2004–2006.
      J Clin Virol. 2007; 38: 27-31
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      Clinical manifestations of human coronavirus NL63 infection in children in Taiwan.
      Eur J Pediatr. 2008; 167: 75-80
      In patients who have croup, HCoV-NL63 infections are detected as frequently as the parainfluenzaviruses, which initially were considered as the main causative agent for this illness.
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      Croup is associated with the novel coronavirus NL63.
      PLoS Med. 2005; 2: 764-770
      Although an additional fascinating disease association was proposed for HCoV-NL63 and Kawasaki disease (the most common form of childhood vasculitis),
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      it could not be confirmed by subsequent investigations.
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      Human coronavirus NL63 is not detected in the respiratory tracts of children with acute Kawasaki disease.
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      Several current indications strongly suggest that HCoV-NL63, in addition to HCoV-229E and HCoV-OC43, is a common cold-causing virus in healthy adults. Actual evidence for this causal relationship is, unfortunately, still lacking.
      In January 2005, a fifth HCoV was discovered in Hong Kong, China. HCoV-HKU1 was recovered from an adult who had chronic pulmonary disease, and it was only distantly related to HCoV-OC43.
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      Clinical symptoms accompanying an HCoV-HKU1 infection include rhinorrhea, fever, cough, febrile seizure, wheezing, pneumonia, and bronchiolitis.
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      • Lau S.K.
      • Chu C.M.
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      Similar to HCoV-NL63, infections with HCoV-HKU1 have been detected worldwide; they presumably are associated with common colds, and most likely cause a more severe clinical spectrum of respiratory disease in young children, adults with underlying disease, or the elderly.
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      Furthermore, there are indications that HCoV-HKU1 also might play a role in GI disease.
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      Koch's postulates

      Once novel viruses are identified, it is important to demonstrate their pathogenic potential and unravel a causal link with a specific disease. Proof of such a relationship ideally would imply fulfilling Koch's postulates, which have been revisited for viral pathogens.
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      These standard criteria propose that a causal connection between a new virus and an illness may be established if:
      • The organism is consistently present in patients who have disease at a higher prevalence than in control patients.
      • The disease is replicated in an appropriate animal model after viral challenge, and subsequently isolated from this animal.
      • A specific host immune response can be demonstrated.
      In the case of HCoV-NL63 and HCoV-HKU1, application of all Koch's postulates turned out to be impossible, and their role in disease therefore remains unconfirmed. Currently, HCoV-HKU1 cannot be maintained in cell culture systems, and animal models are unavailable for both NL63 and HKU1 CoVs. Animal model systems susceptible for HCoV-OC43 and SARS-CoV have been developed previously, and allow present studies of coronaviral tropism, replication, recombination, and accompanying immune modulatory mechanisms.
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      Most recently, a very important technical achievement has been made for studying pathogenic mechanisms of HCoV-NL63, because infectious full-length cDNA clones of the HCoV-NL63 genome can be engineered.
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      Nonetheless, thus far, the only option to identify pathogenic potential of HCoV-NL63 and HCoV-HKU1 is to determine a significant association with a disease through epidemiologic studies with proper control groups.
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      An alternative strategy to gain novel insights in mechanisms of CoV pathogenesis is by extensive characterization of virus–host interactions and host cell invasion strategies. Viral receptor specificity and expression are generally important determinants of the pathogenic potential of a virus and the nature of the disease that it causes.
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      Cellular receptor modulation: a pathway to human coronavirus pathogenesis

      Viral receptors, components that actively promote host cell entry, differ greatly from one virus to the next and constitute a wide variety of proteins and carbohydrates, each with distinct physiologic functions.
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      Although cellular receptors for HCoV-OC43 and HCoV-HKU1 remain to be elucidated, the family of membrane-associated proteases seems to be favored by HCoVs, because both neutral aminopeptidase (APN), the receptor for HCoV-229E,
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      Down-regulation of APN and ACE2 during HCoV-229E, HCoV-NL63, and SARS-CoV infection may impair the normal physiologic function of the host cells severely and contribute to the development of clinical manifestations. Besides their classification as zinc-dependent peptidases, APN and ACE2 share important functional enzymatic characteristics. Both proteins are integral components of the renin–angiotensin system (RAS). This endocrine system is one of the most important regulators of human physiology, with a key role in maintenance of arterial pressure, fluid hemostatis, salt balances, cardiac function, cell proliferation and hypertrophy, angiogenesis, and apoptosis. Therefore, impaired expression of APN and ACE2 also might alter crucial normal physiologic functionalities of the RAS. Most intriguingly, suppression of ACE2 protein expression during SARS-CoV infection actually causes severe imbalances within the enzymatic RAS cascade, which is proposed to be the main cause of severe acute pneumonia and acute lung failure observed during SARS-CoV infection.
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      A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury.
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      , 
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      , 
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      • Kuba K.
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      These findings raise the possibility that CoV-induced dysregulation of the RAS might be important for the clinical outcome of HCoV-229E and HCoV-NL63 infections also.

      Summary

      CoVs are recognized human pathogens, associated with relatively mild upper respiratory tract infections in healthy adults and more serious respiratory complications in weakened patients. A virus-induced modulation of receptor expression could be involved in the onset of CoV-associated clinical symptoms, and future research should focus on elucidation of the physiologic consequences following virus–host interactions. Insight into these processes would contribute to the clarification of the strategies used by HCoVs to elicit specific diseases and might provide a definite demonstration of their etiology also. Eventually, a better understanding of HCoV pathogenesis may lead to development of new therapeutic strategies.

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      Footnotes

      Lia van der Hoek is supported by VIDI grant 016.066.318 from the Netherlands Organization for Scientific Research (NWO).

      Identification

      DOI: https://doi.org/10.1016/j.cll.2009.07.007

      Copyright

      © 2009 Elsevier Inc. Published by Elsevier Inc. All rights reserved.

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