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Invited Minireview The Relationship of Severe Acute Respiratory Syndrome Coronavirus with Avian and Other Coronaviruses Author s Mark W Jackwood Source Avian Diseases Vol 50 No 3 Sep 2006 pp 315 320 Published by American Association of Avian Pathologists Stable URL http www jstor org stable 4099065 Accessed 21 06 2014 22 34 Your use of the JSTOR archive indicates your acceptance of the Terms Accepted 17 May 2006 SUMMARY In February 2003 a severe acute respiratory syndrome coronavirus SARS CoV emerged in humans in Guangdong Province China and caused an epidemic that had severe impact on public health travel and economic trade Coronaviruses are worldwide in distribution highly infectious and extremely difficult to control because they have extensive genetic diversity a short generation time and a high mutation rate They can cause respiratory enteric and in some cases hepatic and neurological diseases in a wide variety of animals and humans An enormous previously unrecognized reservoir of coronaviruses exists among animals Because coronaviruses have been shown both experimentally and in nature to undergo genetic mutations and recombination at a rate similar to that of influenza viruses it is not surprising that zoonosis and host switching that leads to epidemic diseases have occurred among coronaviruses Analysis of coronavirus genomic sequence data indicates that SARS CoV emerged from an animal reservoir Scientists examining coronavirus isolates from a variety of animals in and around Guangdong Province reported that SARS CoV has similarities with many different coronaviruses including avian coronaviruses and SARS CoV like viruses from a variety of mammals found in live animal markets Although a SARS like coronavirus isolated from a bat is thought to be the progenitor of SARS CoV a lack of genomic sequences for the animal coronaviruses has prevented elucidation of the true origin of SARS CoV Sequence analysis of SARS CoV shows that the 5 polymerase gene has a mammalian ancestry whereas the 3 end structural genes excluding the spike glycoprotein have an avian origin Spike glycoprotein the host cell attachment viral surface protein was shown to be a mosaic of feline coronavirus and avian coronavirus sequences resulting from a recombination event Based on phylogenetic analysis designed to elucidate evolutionary links among viruses SARS CoV is believed to have branched from the modern Group 2 coronaviruses suggesting that it evolved relatively rapidly This is significant because SARS CoV is likely still circulating in an animal reservoir or reservoirs and has the potential to quickly emerge and cause a new epidemic RESUMEN Estudio Recapitulativo por Invitaci6n Relaci6n del coronavirus causante del sindrome respiratorio agudo severo con coronavirus aviares y otros coronavirus En Febrero del afio 2003 en la provincia de Guangdong China emergi6 en humanos un coronavirus causante del sindrome respiratorio agudo severo por sus siglas en Ingles SARS CoV que caus6 una epidemia con un impacto severo en la salud puiblica los viajes y el intercambio comercial Los coronavirus tienen distribuci6n mundial son altamente infecciosos y extremadamente dificiles de controlar porque poseen alta diversidad gen6tica periodos cortos de regeneraci6n y una alta tasa de mutaci6n Pueden causar enfermedades respiratorias entericas y en algunos casos enfermedades hepiticas y neurol6gicas en una amplia variedad de animales y en humanos Entre los animales existe un enorme reservorio de coronavirus no reconocido con anterioridad Debido a que se ha demostrado experimentalmente y en la naturaleza que los coronavirus son capaces de sufrir mutaciones y recombinaciones gen6ticas a una tasa similar a la de los virus de influenza no es sorprendente que el cambio de hubsped y la zoonosis que conlleva a enfermedades epidemicas hayan ocurrido entre los coronavirus El anlisis de la secuencia del genoma del SARS CoV indica que este emergi6 de un reservorio animal Analizando los aislamientos de coronavirus provenientes de una variedad de animales dentro y en los alrededores de la provincia de Guandong los cientificos reportaron que SARS CoV tiene similitudes con diferentes coronavirus incluyendo coronavirus aviares y virus parecidos a SARS CoV provenientes de una variedad de mamiferos hallados en mercados de animales vivos Aun cuando se piensa que un virus parecido al SARS CoV aislado en un murcielago es el progenitor del SARS CoV la inexistencia de secuencias de los coronavirus de este animal ha impedido elucidar el verdadero origen del SARS CoV El analisis de la secuencia del SARS CoV muestra que el gen 5 de la polimerasa tiene un ancestro mamifero mientras que los genes estructurales del extremo 3 excluyendo la glicoproteina de la espicula tienen un origen aviar Se ha demostrado que la glicoproteina de la espicula que es la proteina viral de superficie que permite el contacto con el hubsped es un mosaico de secuencias de coronavirus felinos y coronavirus aviares resultante de un evento de recombinaci6n Basaindose en andlisis filogeneticos disefiados para elucidar las interrelaciones evolutivas entre virus se cree que el SARS CoV se separ6 del grupo 2 de coronavirus modernos sugiriendo que evolucion6 relativamente raipido Esto es muy significativo porque es probable que el SARS CoV aun est6 circulando en un reservorio o reservorios animales y tiene el potencial de emerger ripidamente y causar una nueva epidemia Key words severe acute respiratory syndrome avian coronavirus phylogenetic relationship molecular evolution mutation recombination animal reservoir emergence SARS CoV infectious bronchitis virus turkey coronavirus Abbreviations BCoV bovine coronavirus E envelope FIPV feline infectious peritonitis virus HCoV human coronavirus HE hemagglutinin esterase IBV infectious bronchitis virus M membrane MHV mouse hepatitis virus N nucleocapsid PEDV porcine epidemic diarrhea virus RBD receptor binding domain RdRp RNA dependent RNA polymerase S spike SARS severe acute respiratory syndrome SARS CoV severe acute respiratory syndrome coronavirus TCoV turkey coronavirus TGEV transmissible gastroenteritis virus 315 This content downloaded from 62 122 72 154 on Sat 21 Jun 2014 22 34 02 PM All use subject to JSTOR Terms and Conditions 316 M W Jackwood Intensive animal agriculture practices human population growth and cultural habits and customs have put humans in close contact with animal reservoirs of viruses that have the potential to cause zoonotic diseases In February 2003 severe acute respiratory syndrome SARS in humans was reported in Guangdong Province the People s Republic of China The etiological agent of SARS was quickly identified as a newly emerged coronavirus but not before the disease spread to over 24 countries in only a few months infecting 8098 people worldwide and killing 774 World Health Organization http www who int csr sars en 10 30 36 It is widely believed that the SARS coronavirus SARS CoV originated from an animal reservoir but the true origin of the virus is still unknown 23 28 There is a newly recognized reservoir of coronaviruses that exists among animals Because coronaviruses have been shown both experimentally and in nature to undergo genetic recombination by a genomic template switching mechanism and to generate genetic point mutations at a rate similar to that of other RNA viruses includ ing influenza A viruses it is not surprising that zoonosis and host switching leading to epidemic diseases occur among coronaviruses It should be noted that coronaviruses among wildlife and domestic animals can also pose a threat to the health of commercial poultry Many questions regarding coronavirus origin evolution and genetic diversity can be answered in part from phylogenetic and evolutionary analysis of genome sequence data Since the first report of SARS CoV scientists have been examining coronavirus isolates from a variety of animals in and around Guangdong Province in an attempt to identify natural host reservoirs and determine their roles in propagation evolution and transmission of these viruses Geno mic sequence analysis of SARS CoV shows similarities with many different coronaviruses including avian coronaviruses and SARS CoV like viruses from a variety of mammals found in live animal markets in China 22 39 However a lack of genomic sequences for animal coronaviruses has hindered efforts to identify the true origin of the SARS CoV That information is essential if we are to prevent future coronavirus outbreaks Coronaviral diseases Coronaviruses are worldwide in dis tribution and highly infectious by nature They cause respiratory enteric and in some cases hepatic and neurological diseases in a wide variety of animals and humans 25 The diseases can be acute or chronic and can be transmitted by respiratory or enteric routes Most coronaviruses replicate in the epithelial cells of the upper respiratory tract and the enteric tract causing respiratory disease and diarrhea Other sites of infection in the host can include the kidney re productive tract liver spleen thymus and brain 18 25 The disease caused by the SARS CoV is characterized by a lower respiratory tract infection accompanied by high fever headache loss of appetite and diarrhea in about 10 20 percent of patients 1 34 35 At the onset a mild respiratory disease is observed with a dry cough that usually develops into pneumonia after 7 days 19 The SARS CoV is primarily transmitted by respiratory aerosol but the virus is also shed in the feces making fecal oral transmission a possibility 48 The virus can infect nonhuman primates civet cats domestic cats ferrets mice and golden Syrian hamsters whereas pigs and chickens are refractory to infection 42 47 48 The avian coronaviruses infectious bronchitis virus IBV and turkey coronavirus TCoV are known to cause a respiratory disease in chickens and enteric disease in turkeys respectively 8 15 Infectious bronchitis in chickens is a mild disease characterized by watery eyes catarrhal tracheitis swollen sinuses sneezing coughing and tracheal rales Turkey coronavirus causes a severe diarrhea in poults less than 4 wk of age and has been associated with poult en teritis and mortality syndrome 16 The clinical signs can include depression anorexia and dehydration as a result of a watery diar Group 1 RdRp 3b A Group 2 RdRp 4 4 9 4 8 E HE S SARS CoV RdRp S 33 67 b IAn Group 3 RdRp S 3a 3b E 5a 5b IAn Fig 1 Gene organization for the three groups of coronaviruses and for SARS CoV The gray boxes depict open reading frames coding for known viral proteins and are showing gene order only they are not to scale An polyA tail rhea which can contain urates and mucus The lower intestines including the ceca are often thin walled and pale 14 Chickens are the only animals naturally infected by IBV and TCoV infects turkeys of all ages and possibly chickens but only young turkeys develop clinical disease 6 14 Coronaviruses Coronaviruses are enveloped viruses contain ing the largest 28 to 30 kb single stranded positive sense RNA genome known 18 The shape of the virion is pleomorphic and thus varies in diameter from 80 nm to 100 nm The major proteins encoded by the viral genome are in order starting at the 5 end the viral polymerase open reading frames la and ib hemagglutinin esterase HE in some viruses the spike S glycoprotein located on the surface of the virus a small envelope protein E an integral membrane glycoprotein M and the nucleocapsid protein N which is closely associated with the viral RNA Several nonstructural and regulatory proteins are also encoded by the viral genome see Fig 1 Coronaviruses belong to the family Coronaviridae in the Nidovirales order 11 Other families in the Nidovirales order are Arteviridae and Roniviridae which include viruses that infect swine and equine and viruses that infect invertebrates respectively Coro naviruses are divided into three groups based on antigenicity and genetic structure see Fig 1 25 Group I viruses include among others transmissible gastroenteritis virus TGEV in pigs feline infectious peritonitis virus FIPV canine coronavirus human coronavirus HCoV strain 229E and porcine epidemic diarrhea virus PEDV The viruses in Group I do not have an HE protein the M protein is N glycosylated and the S glycoprotein is not cleaved Some examples of Group II coronaviruses are mouse hepa titis virus MHV bovine coronavirus BCoV and HCoV strain OC43 Most of the coronavirus in Group II have an HE protein the M protein is O glycosylated and the S glycoprotein is cleaved into two subunits The Group III coronaviruses include the avian coronaviruses IBV TCoV and pheasant coronavirus Viruses in Group III do not have an HE protein the M protein is N glycosylated and the S glycoprotein is cleaved Based on sequence analysis of the polymerase protein the SARS CoV is currently This content downloaded from 62 122 72 154 on Sat 21 Jun 2014 22 34 02 PM All use subject to JSTOR Terms and Conditions SARS avian and other coronaviruses 317 placed as a distant member of the Group II coronaviruses However like Group III avian coronaviruses it does not have an HE protein and the SARS CoV membrane protein is N glycosylated and the S glycoprotein was shown to be cleaved in vitro 44 51 It is also interesting to note that the gene organization of the 3 end of the SARS CoV genome is most similar to the Group III avian viruses Fig 1 The most studied coronavirus structural protein is the S glycoprotein The S glycoprotein forms club shaped projections on the surface of the virus particles It is anchored in the viral enve lope and in Group II and III coronaviruses it is posttranslationally cleaved by host cell serine proteases into two subunits designated S 1 and S2 The S glycoprotein mediates host cell attachment and entry Generally coronaviruses bind to specific host cell receptors and several have been identified The SARS CoV binds to angiotensin converting enzyme 2 whereas the avian coronaviruses utilize sialic acid alpha 2 3 linked to galactose and possibly a secondary receptor protein aminopeptidase N or other protein to attach and enter cells 25 27 31 49 50 When the S glycoprotein binds to its specific cell receptor it undergoes a conformation change involving two heptad repeat regions that brings the S glycoprotein fusion peptide in close proximity to the viral transmembrane segment which facil itates membrane fusion and entry into the cell 2 The S glycoprotein plays a role in the pathogenesis of the virus 3 25 48 A receptor binding domain RBD within the amino terminus of the S glycoprotein forms part of the globular head of the mature protein The RBD of SARS CoV residues 318 510 maps to the hypervariable region III in IBV residues 274 387 which is associated with neutralizing epitopes on the S glycoprotein 32 50 Changes in the S glycoprotein and specifically in the RBD can alter host cell specificity and mediate shifts in viral pathogenesis 17 24 37 Replacing the S glycoprotein gene of an attenuated respiratory strain of TGEV with the S glycoprotein from a patho genic enteric strain changed the respiratory strain into a pathogenic enterotropic virus in pigs 37 Changes in the S glycoprotein can also lead to host switching Using targeted recombination the MHV S glycoprotein gene was substituted for the FIPV S glycoprotein and the recombinant feline MHV containing the feline S glycoprotein was now capable of infecting feline cells and lost its ability to infect murine cells 24 A host shift was also observed when TCoV which is closely related to IBV acquired a S glycoprotein gene of unknown origin allowing it to emerge and cause enteric disease in turkeys 20 However pathogenicity does not appear to be solely related to the S glycoprotein in some coronaviruses For example when the ecto domain of the S glycoprotein gene in the nonpathogenic Beaudette strain of IBV was replaced with the S glycoprotein from a pathogenic strain of the same serotype Mass 41 no difference in pathogenicity was observed between the recombinant and the parental strain 17 Viral replication and genetic diversity Coronaviruses have a short generation time and a high mutation rate which provides the virus with extensive genetic diversity making it ex tremely difficult to control To understand how genetic diversity is achieved in coronaviruses it is necessary to know how the virus replicates After attachment and entry into the cell the positive sense viral genome acts as a messenger RNA mRNA for the transcription of the viral RNA dependent RNA polymerase RdRp Then using a leader primed mRNA synthesis mechanism the polymerase gen erates a 3 coterminal nested set of subgenomic sized mRNAs that code for the other viral proteins The polymerase also replicates the full length viral genome by the same mechanism During this pro cess the polymerase can generate genetic diversity by two means First the RdRp does not have proofreading capabilities so it cannot fix mistakes made while copying the viral genome The RdRp is estimated to generate mutations at a rate of 5 7 X 10 6 nucleotide substitutions per site per day or 0 17 mutations per genome per day which is similar to rates reported for avian influenza viruses 40 43 Second the RdRp can also produce genetic diversity by a template switching mechanism 5 When two or more different strains of coronavirus enter the same cell recombination can occur as a result of switching templates from one viral genome to another In this way whole genes or genome segments can be exchanged between viruses This was shown to occur in vaccine strains in the field 21 and in a natural outbreak of IBV in Texas where a hot spot for recombination was identified in the S1 gene 45 46 A recent ex ample of template switching occurred in the avian coronaviruses and led to the emergence of TCoV Analysis of the TCoV S glycoprotein gene showed the S1 portion to be genetically unique with a putative recombination crossover site identified in the 5 end of the S2 gene 20 The other genes 3ab M 5ab and N downstream of the crossover site including the majority of the S2 gene were nearly identical to IBV 4 7 14 20 The ancestor of TCoV is clearly IBV but the origin of the TCoV S glycoprotein gene which allowed that virus to emerge and cause disease in turkeys is not known SARS CoV genetic similarity with IBV TCoV and other coronaviruses Recombination events contribute to the evolu tion and emergence of coronaviruses by creating mosaic viruses A BLAST analysis www ncbi nlm nih gov BLAST as well as phylo genetic and recombination studies of the SARS CoV genome showed similarities with IBV BCoV HCoV 229E MHV PEDV and TGEV 52 Stavrinides and Guttman 39 using Bayesian neighbor joining and split decomposition phylogenetic analysis of the full length SARS CoV genome showed that the polymerase protein 5 region of the genome had a mammalian ancestry and was most closely related to the Group II coronaviruses In addition they found evidence that the M and N proteins 3 region of the genome had an avian coronavirus origin which was also shown by Marra et al 30 Because the S glycoprotein mediates cell attach ment and is responsible for host specificity it was interesting that the SARS CoV S gene was found to be a mosaic containing both avian infectious bronchitis virus Group III and feline infectious perito nitis virus Group I sequences 39 The feline sequences evident in the first 600 residues are interesting because palm civet cats appear to play a role in the epidemiology of this disease The IBV related sequences were evident between residues 601 and 667 suggesting that a recombination event occurred in the middle of the S glycoprotein gene which may have contributed to the observed shift in host range It is unclear which animal may have been the inter mediary host Phylogenetic studies on TCoV conducted in our laboratory showed that sequences in the TCoV S glycoprotein were also found in the SARS CoV 20 Similarit