The discovery that a novel coronavirus is the probable cause of the newly recognized severe acute respiratory syndrome (SARS), reported by Ksiazek et al. (pages 1953–1966), Drosten et al. (pages 1967–1976), and Peiris et al.1 provides a dramatic example of an emerging coronavirus disease in humans, described by Poutanen et al. (pages 1995–2005), Tsang et al. (pages 1977–1985), and Lee et al. (pages 1986–1994). Although human coronaviruses cause up to 30 percent of colds, they rarely cause lower respiratory tract disease. In contrast, coronaviruses cause devastating epizootics of respiratory or enteric disease in livestock and poultry
Most coronaviruses cause disease in only one host species. All known coronaviruses are found in three serologically unrelated groups. The Figure shows the structure of the virion. The message-sense RNA genome and the viral nucleocapsid phosphoprotein form a helical nucleocapsid. A corona of large, distinctive spikes in the envelope makes possible the identification of coronaviruses by electron microscopy. The spikes, oligomers of the spike(S) glycoprotein, bind to receptors on host cells and fuse the viral envelope with host cell membranes. Coronaviruses in group 2 also have a hemagglutinin–acetylesterase (HE) glycoprotein that binds to sugar moieties on cell membranes. Curiously, the gene for HE was apparently introduced into an ancestral coronavirus genome by recombination with the messenger RNA encoding HE of influenza C. The unique RNA-dependent RNA polymerase of coronaviruses often switches template strands during replication, causing RNA recombination when a cell is infected with several coronaviruses. This error-prone polymerase also generates point mutations and large deletions or insertions of foreign RNA into the viral genome.
The SARS-associated coronavirus could have arisen as a mutant of a human coronavirus that acquired new virulence factors, as a mutant of an animal coronavirus that can infect human cells, or as a recombinant of two human coronaviruses or a human coronavirus and an animal coronavirus. Antibodies to the SARS-associated coronavirus were found in serum samples obtained from patients with SARS during convalescence but not in human serum samples banked before the SARS outbreak, suggesting that the SARS-associated coronavirus is new to the human population. The nucleotide sequence of the SARS-associated coronavirus genome (http://www.bcgsc.ca/bioinfo/SARS. opens in new tab; http://www.cdc.gov/ncidod/sars/sequence.htm. opens in new tab) differs substantially from sequences of all known coronaviruses.
Thus, the SARS-associated coronavirus is neither a mutant of any known coronavirus nor a recombinant of known coronaviruses. It is a previously unknown coronavirus, probably from a nonhuman host, that somehow acquired the ability to infect humans. Serologic tests of wild and domestic animals and birds in the region where the outbreak first appeared may identify the usual host. Comparison of isolates of the SARS-associated coronavirus from infected patients and from the natural host may reveal how the virus jumped to humans. In jumping to humans, did the SARS-associated coronavirus lose the ability to infect its original host? If there is no animal reservoir, there will be a better chance of eliminating the virus from humans.
The host range, tissue tropism, and virulence of animal coronaviruses can be changed by mutations in the S gene. The sequence of the S gene in the SARS-associated coronavirus may suggest how S glycoprotein affects the pathogenesis of SARS. The SARS-associated coronavirus genome sequence shows that it does not contain a gene encoding HE or large genes derived from another virus or host cell. It is an amazing feat that the SARS-associated coronavirus genome has been completely sequenced so quickly. The surprising discovery that the virus can be readily isolated in a monkey-kidney cell line was the key to the rapid molecular characterization of this novel coronavirus and the development of diagnostic tests for SARS. SARS-associated coronavirus has recently been proved to be the cause of SARS. Inoculation of monkeys with SARS-associated coronavirus from cell cultures caused lower respiratory tract disease, fulfilling Koch's postulate.
Both viral and host factors affect the virulence of coronavirus diseases in animals. The disease is usually most severe in neonates. The signs of infection in immunosuppressed animals may differ from those in immunocompetent animals; immunosuppressed animals may also shed virus for prolonged periods and accumulate and possibly spread mutant viruses. The detection of SARS-associated coronavirus in fecal and serum samples from patients, as well as in respiratory specimens, suggests that this virus, like many animal coronaviruses, may be spread both by fecal contamination and by respiratory droplets. Host genes that affect the viral receptor, viral production, and immune responses to infection can determine the outcome of coronavirus infections, making certain species or strains of animals highly susceptible to lethal infection. For example, coronaviruses from domestic cats almost always cause death in cheetahs. Coinfection with other viruses, parasites, or bacteria exacerbates some animal coronavirus diseases. The deaths of 3 to 4 percent of patients with SARS may result from host factors that exacerbate the disease.
Although there are no approved drugs with proven efficacy against coronaviruses, there are potential targets for the development of new drugs. Protease inhibitors could prevent processing of the RNA polymerase or cleavage of the viral S glycoprotein. Inhibitors of coronavirus acetylesterase activity might limit viral replication, as neuraminidase inhibitors inhibit the replication of influenzaviruses A and B. Inhibitors of membrane fusion might block viral entry, as do several new drugs against the human immunodeficiency virus. Antibodies against the viral S glycoprotein or the unidentified receptor for the SARS-associated coronavirus might also block entry of the virus.
Vaccines are available for some animal coronaviruses. Vaccination with live, attenuated virus is effective against porcine epidemic diarrhea virus and avian infectious bronchitis virus. However, recombination of genomes of vaccine strains with wild-type coronaviruses is a potential risk associated with using live, attenuated coronavirus vaccines in humans. Killed or subunit vaccines containing the spike glycoprotein, perhaps with other viral proteins, might prevent lower respiratory tract disease in humans. However, some vaccines against feline coronaviruses actually enhanced disease when vaccinated animals were exposed to wild-type virus, and antibody enhancement of disease is a potential risk of SARS vaccines in humans. It is possible that the current outbreak may be controlled and the virus eliminated by quarantine alone. Nevertheless, it is prudent to develop safe, effective drugs and vaccines against the Urbani SARS-associated coronavirus as quickly as possible, in case the outbreak cannot be contained. The development of drugs and vaccines for SARS will also provide new strategies for the prevention and treatment of other coronavirus diseases of animals and humans.
