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Comparative analysis of the SARS coronavirus genome: a good start to a long journey

2003; Elsevier BV; Volume: 361; Issue: 9371 Linguagem: Inglês

10.1016/s0140-6736(03)13444-7

1474-547X

Earl G. Brown, Jason A. Tetro,

Viral gastroenteritis research and epidemiology

Published online May 9, 2003 http://image.thelancet.com/extras/03cmt124web.pdf Severe acute respiratory syndrome (SARS) is the latest in a long list of emerging infectious diseases to gain the attention not only of the scientific community but also of the general public. SARS is characterised by symptoms that include a temperature over 38°C, dry cough, myalgia, and mild sore throat, which progresses to atypical pneumonia. The disease is unusual in its high morbidity and mortality rates; and it mimics and indeed rivals the 1918 influenza pandemic, which still stands as the worst pandemic in history.1Luk J Gross P Thompson WW Observations on mortality during the 1918 influenza pandemic.Clin Infect Dis. 2001; 33: 1375-1378Crossref PubMed Scopus (125) Google Scholar More disturbingly, SARS seems to transmit through direct contact and extreme infection-control measures are thus needed in affected areas.2World Health Organization Hospital infection control guidance for severe acute respiratory syndrome (SARS). April 24, 2003http://www.who.int/csr/sars/infectioncontrol/en/Google Scholar Although SARS currently has no absolutely confirmed cause, a first approximation of Koch's postulates has been satisfied for a newly discovered virus within the family Coronaviridae.3Peiris JSM Lai ST Poon LLM et al.Coronavirus as a possible cause of severe acute respiratory syndrome.Lancet. 2003; 361: 1319-1325Summary Full Text Full Text PDF PubMed Scopus (2474) Google Scholar, 4Ksiazek TG Erdman D Goldsmith CS et al.A novel coronavirus associated with severe acute respiratory syndrome.N Engl J Med. 2003; 348: 1953-1966Crossref PubMed Scopus (3554) Google Scholar This newly identified virus has been designated SARS coronavirus (SARS-CoV).5World Health Organization Update 31: coronavirus never before seen in humans is the cause of SARS. April 16, 2003http://www.who.int/csr/sarsarchive/2003_04_16/en/Google Scholar Coronaviruses are large enveloped viruses with a positive-sense RNA genome ranging in size from 27 to 30 kb, the largest of any of the RNA viruses. Clinically speaking, coronaviruses are usually associated with the common cold in human beings, but in animals the virus can lead to highly virulent respiratory, enteric, and neurological diseases as well as hepatitis.6Lai MMC Holmes KV Coronaviridae: the viruses and their replication.in: Knipe DM Howley PM Fields virology. 4th edn. Lippincott Williams & Wilkins, London2001: 1163-1186Google Scholar Human coronaviruses are usually difficult to culture in vitro, whereas most animal coronaviruses and SARS-CoV can be easily cultured in Vero E6 cells.7Drosten C Gönther S Preiser W et al.Identification of a novel coronavirus in patients with severe acute respiratory syndrome.N Engl J Med. 2003; (accessed May 6, 2003).http://content.nejm.org/cgi/content/abstract/NEJMoa03747v2Crossref PubMed Scopus (3676) Google Scholar Recently, in a Canadian collaborative tour de force, the Michael Smith Genome Sciences Centre in Vancouver, British Columbia, and the National Microbiology Laboratory in Winnipeg, Manitoba, were the first to obtain a full sequence of SARS-CoV.8Rota PA Oberste MS Monroe SS Characterization of a novel coronavirus associated with severe acute respiratory syndrome.Science. 2003; (accessed May 6, 2003).http://www.sciencemag.org/cgi/rapidpdf/108595v1.pdfCrossref PubMed Scopus (2182) Google Scholar, 9Marra MA Jones SJM Astell CR et al.The genome sequence of the SARS-associated coronavirus.Science. 2003; (accessed May 6, 2003).http://www.sciencemag.org/cgi/rapidpdf/1085953v1.pdfCrossref PubMed Scopus (1815) Google Scholar With 29 751 bases, the genome, denoted Tor-2, possesses a classic coronavirus complement of 11 open-reading frames, S and E glycoproteins, and the matrix, replicase, and nucleocapsid proteins. However, at the aminoacid level, SARS-CoV has minimum homology with any of the three classes of coronavirus; SARS-CoV thus lies in its own group.9Marra MA Jones SJM Astell CR et al.The genome sequence of the SARS-associated coronavirus.Science. 2003; (accessed May 6, 2003).http://www.sciencemag.org/cgi/rapidpdf/1085953v1.pdfCrossref PubMed Scopus (1815) Google Scholar In today's Lancet, YiJun Ruan and colleagues take the sequences of five SARS strains of known passage history in human beings and compare them with the Tor-2 sequence as well as other fully sequenced SARS-CoV strains from China and Vietnam. In addition to identifying small clusters of inherited mutations that are lineage-specific and can be used as molecular signatures to track transmission, the results suggest a remarkable genetic conservation of the virus since the outbreak was first documented in February, 2003. Although there are a handful of mutations between isolates, they may be due to adaption in culture. Previous experience with the evolution of influenza A virus shows that such "end-of-lineage" changes are due to mutations selected in laboratory culture.10Bush RM Smith CB Cox NJ Fitch WM Effects of passage history and sampling bias on phylogenetic reconstruction of human influenza A evolution.Proc Natl Acad Sci USA. 2000; 97: 6974-6980Crossref PubMed Scopus (69) Google Scholar In Ruan's study, most of the mutations in the SARS-CoV sequences probably represent adaption to Vero cells during propagation before sequencing. It can therefore be concluded that as the virus passes through human beings, SARS-CoV is maintaining its consensus genotype and is thus well adapted to the human host. This finding may indeed be a double-edged sword. SARS-CoV is not likely to change rapidly and thus may not readily mutate to a benign infection, as seen with most other infectious agents transmitted by direct contact and where patients'mobility is crucial to facilitate transfer of disease. Any disease property that enhances transmission to new hosts will be the subject of positive evolutionary selective pressures.11Ewald PW The evolution of virulence and emerging diseases.J Urban Health. 1998; 75: 480-491Crossref PubMed Google Scholar Experimental analysis of viral evolution shows that genomic stability in a specific host is a function of viral population size-passage of large populations results in increased replicative fitness and virulence due to the competitive selection of optimising mutations.12Brown EG Liu H Kit LC Baird S Nesrallah M Pattern of mutation in the genome of influenza A virus on adaptation to increased virulence in the mouse lung: identification of functional themes.Proc Natl Acad Sci USA. 2001; 98: 6883-6888Crossref PubMed Scopus (162) Google Scholar By contrast, passage of limiting dosages results in decreased replicative fitness and attenuation due to the adventitious trapping of deleterious mutations. The hope with SARS-CoV is that it will attenuate its properties in human beings. Sadly, Ruan and colleagues'results suggest that this attenuation does not seem to be happening at a rapid rate and may indicate a worrisome epidemiological trend. Yet, there may be a bright side to the evidence reported by Ruan and colleagues. The apparent genetic stability makes a vaccine seem more achievable. However, coronaviruses can transduce genes from foreign genomes, recombine with other coronaviruses, and mutate to drive rapid and extreme evolution-presumably SARS-CoV is a product of such evolution. Furthermore, SARS-CoV was found in the faeces of patients,3Peiris JSM Lai ST Poon LLM et al.Coronavirus as a possible cause of severe acute respiratory syndrome.Lancet. 2003; 361: 1319-1325Summary Full Text Full Text PDF PubMed Scopus (2474) Google Scholar which indicates more than one tissue tropism. This discovery also raises the slight possibility of transmission through water in which the property of high virulence can be maintained under conditions that allow untreated sewage contamination of surface and ground waters.11Ewald PW The evolution of virulence and emerging diseases.J Urban Health. 1998; 75: 480-491Crossref PubMed Google Scholar In addition, animal and human experiences with coronaviruses have illustrated a range of problems, including a lack of protective immunity, persistent infection, and immune enhancement (in which antiviral antibodies increase disease progression). This latter problem may explain in part the relatively high mortality rate. If a vaccine is possible, there is a long way to go. There is also one more very puzzling aspect to the SARS story, which comes to the heart of the confusion and concern in the scientific and medical communities. Where and how did SARS arise? A great deal of retrospective isolation and genomic sequencing of human and animal coronaviruses, especially in the virological hotbed of southern China, is required for the molecular sleuthing needed to solve this puzzle. SARS-CoV possesses a novel organisation of five open-reading frames that encode proteins with as yet unknown functions which, from experience with other viruses, may encode antagonists of innate and adaptive immunity.13Seo SH Hoffmann E Webster RG Lethal H5N1 influenza viruses escape host anti-viral cytokine responses.Nat Med. 2002; 8: 950-954Crossref PubMed Scopus (610) Google Scholar Much like the human genome, the SARS-CoV genetic code charts a detailed roadmap through unknown territories. Molecular virologists now need to interpret gene function from this genetic sequence, which will not be easy given that single aminoacid changes can dramatically affect biological function. As the SARS outbreak looks to be contained in the more technologically advanced regions of the world, complacency must be avoided. That a coronavirus with high virulence has arisen should not be a surprise, because historically the worst epidemics of respiratory disease have come from the influenza A viruses, which ominously share several biological features with coronaviruses. Both viruses are zoonoses, both have instances of dual tropism for respiratory and gastrointestinal tissues, and, most importantly, both possess mechanisms for the generation of extreme genetic variability. Models of influenza might guide the understanding of the SARS coronavirus.14Fields BN AIDS: time to turn to basic science.Nature. 1994; 369: 95-96Crossref PubMed Scopus (26) Google Scholar There is a short period of grace in which to combat SARS. The major questions about SARS-CoV control and biology, such as mode of transmission, spread, and mechanisms of virulence, need answering—before the next time SARS rears its ugly corona. Comparative full-length genome sequence analysis of 14 SARS coronavirus isolates and common mutations associated with putative origins of infectionDespite the recent onset of the SARS epidemic, genetic signatures are emerging that partition the worldwide SARS viral isolates into groups on the basis of contact source history and geography. These signatures can be used to trace sources of infection. In addition, a common variant associated with a non-conservative aminoacid change in the S1 region of the spike protein, suggests that immunological pressures might be starting to influence the evolution of the SARS virus in human populations. Published online May 9, 2003 http://image.thelancet.com/extras/03art4454web.pdf Full-Text PDF