The discovery that a novel coronavirus is the probable causeof the newly recognized severe acute respiratory syndrome (SARS),reported by Ksiazek et al. (pages 1953–1966), Drostenet al. (pages 1967–1976), and Peiris et al.1 providesa dramatic example of an emerging coronavirus disease in humans,described by Poutanen et al. (pages 1995–2005), Tsanget 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 orenteric disease in livestock and poultry.
Most coronaviruses cause disease in only one host species. Allknown coronaviruses are found in three serologically unrelatedgroups. The Figure shows the structure of the virion. The message-senseRNA genome and the viral nucleocapsid phosphoprotein form ahelical nucleocapsid. A corona of large, distinctive spikesin the envelope makes possible the identification of coronavirusesby electron microscopy. The spikes, oligomers of the spike(S)glycoprotein, bind to receptors on host cells and fuse the viralenvelope with host cell membranes. Coronaviruses in group 2also have a hemagglutinin–acetylesterase (HE) glycoproteinthat binds to sugar moieties on cell membranes. Curiously, thegene for HE was apparently introduced into an ancestral coronavirusgenome by recombination with the messenger RNA encoding HE ofinfluenza C. The unique RNA-dependent RNA polymerase of coronavirusesoften switches template strands during replication, causingRNA recombination when a cell is infected with several coronaviruses.This error-prone polymerase also generates point mutations andlarge deletions or insertions of foreign RNA into the viralgenome.
The SARS-associated coronavirus could have arisen as a mutantof 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 coronavirusand an animal coronavirus. Antibodies to the SARS-associatedcoronavirus were found in serum samples obtained from patientswith SARS during convalescence but not in human serum samplesbanked before the SARS outbreak, suggesting that the SARS-associatedcoronavirus is new to the human population. The nucleotide sequenceof the SARS-associated coronavirus genome (http://www.bcgsc.ca/bioinfo/SARS;http://www.cdc.gov/ncidod/sars/sequence.htm) differs substantiallyfrom sequences of all known coronaviruses.
Thus, the SARS-associated coronavirus is neither a mutant ofany known coronavirus nor a recombinant of known coronaviruses.It is a previously unknown coronavirus, probably from a nonhumanhost, that somehow acquired the ability to infect humans. Serologictests of wild and domestic animals and birds in the region wherethe outbreak first appeared may identify the usual host. Comparisonof isolates of the SARS-associated coronavirus from infectedpatients and from the natural host may reveal how the virusjumped to humans. In jumping to humans, did the SARS-associatedcoronavirus lose the ability to infect its original host? Ifthere is no animal reservoir, there will be a better chanceof eliminating the virus from humans.
The host range, tissue tropism, and virulence of animal coronavirusescan be changed by mutations in the S gene. The sequence of theS gene in the SARS-associated coronavirus may suggest how Sglycoprotein affects the pathogenesis of SARS. The SARS-associatedcoronavirus genome sequence shows that it does not contain agene encoding HE or large genes derived from another virus orhost cell. It is an amazing feat that the SARS-associated coronavirusgenome has been completely sequenced so quickly. The surprisingdiscovery that the virus can be readily isolated in a monkey-kidneycell line was the key to the rapid molecular characterizationof this novel coronavirus and the development of diagnostictests for SARS. SARS-associated coronavirus has recently beenproved to be the cause of SARS. Inoculation of monkeys withSARS-associated coronavirus from cell cultures caused lowerrespiratory tract disease, fulfilling Koch's postulate.
Both viral and host factors affect the virulence of coronavirusdiseases in animals. The disease is usually most severe in neonates.The signs of infection in immunosuppressed animals may differfrom those in immunocompetent animals; immunosuppressed animalsmay also shed virus for prolonged periods and accumulate andpossibly spread mutant viruses. The detection of SARS-associatedcoronavirus in fecal and serum samples from patients, as wellas in respiratory specimens, suggests that this virus, likemany animal coronaviruses, may be spread both by fecal contaminationand by respiratory droplets. Host genes that affect the viralreceptor, viral production, and immune responses to infectioncan determine the outcome of coronavirus infections, makingcertain species or strains of animals highly susceptible tolethal infection. For example, coronaviruses from domestic catsalmost always cause death in cheetahs. Coinfection with otherviruses, parasites, or bacteria exacerbates some animal coronavirusdiseases. The deaths of 3 to 4 percent of patients with SARSmay result from host factors that exacerbate the disease.
Although there are no approved drugs with proven efficacy againstcoronaviruses, there are potential targets for the developmentof new drugs. Protease inhibitors could prevent processing ofthe RNA polymerase or cleavage of the viral S glycoprotein.Inhibitors of coronavirus acetylesterase activity might limitviral replication, as neuraminidase inhibitors inhibit the replicationof influenzaviruses A and B. Inhibitors of membrane fusion mightblock viral entry, as do several new drugs against the humanimmunodeficiency virus. Antibodies against the viral S glycoproteinor the unidentified receptor for the SARS-associated coronavirusmight also block entry of the virus.
Vaccines are available for some animal coronaviruses. Vaccinationwith live, attenuated virus is effective against porcine epidemicdiarrhea virus and avian infectious bronchitis virus. However,recombination of genomes of vaccine strains with wild-type coronavirusesis a potential risk associated with using live, attenuated coronavirusvaccines in humans. Killed or subunit vaccines containing thespike glycoprotein, perhaps with other viral proteins, mightprevent lower respiratory tract disease in humans. However,some vaccines against feline coronaviruses actually enhanceddisease when vaccinated animals were exposed to wild-type virus,and antibody enhancement of disease is a potential risk of SARSvaccines in humans. It is possible that the current outbreakmay be controlled and the virus eliminated by quarantine alone.Nevertheless, it is prudent to develop safe, effective drugsand vaccines against the Urbani SARS-associated coronavirusas quickly as possible, in case the outbreak cannot be contained.The development of drugs and vaccines for SARS will also providenew strategies for the prevention and treatment of other coronavirusdiseases of animals and humans.
Source Information
From the University of Colorado Health Sciences Center, Denver.
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