animal coronaviruses: what can they teach us about the ......animal coronaviruses: what can they...

Rev. sci. tech. Off. int. Epiz., 2004, 23 (2), 643-660

Animal coronaviruses: what can they teach usabout the severe acute respiratory syndrome?

L.J. Saif

Food Animal Health Research Program, Ohio Agricultural Research & Development Center (OARDC), OhioState University, Wooster, OH 44691, United States of America

SummaryIn 2002, a new coronavirus (CoV) emerged in the People’s Republic of China,associated with a severe acute respiratory syndrome (SARS) and mortality inhumans. The epidemic rapidly spread throughout the world before beingcontained in 2003, although sporadic cases occurred thereafter in Asia. The virusis thought to be of zoonotic origin from a wild animal reservoir (Himalayan palmcivets [Paguma larvata] are suspected), but the definitive host is unknown. Thereis concern about possible transmission of SARS CoV to rodents or domestic cats(as proven experimentally) with perpetuation of the disease in these species. Inlivestock and poultry, CoVs are recognised causes of enteric and respiratoryinfections that are often fatal in young animals. Although the emergence of SARSsurprised the medical community, veterinary coronavirologists had previouslyisolated CoVs from wildlife and documented their interspecies transmission tolivestock. Furthermore, scientists were aware of compelling evidence pointing tothe emergence of new CoV strains and the mutation of existing strains resultingin new disease syndromes in animals, but the evolution and disease impact ofCoVs was not widely appreciated before SARS. This review focuses on thecomparative pathogenesis of CoV infections, including the factors thataccentuate CoV respiratory disease, with emphasis on livestock and poultry. Thegoal is to provide insights into CoV transmission and disease mechanisms thatcould potentially be applicable to SARS, highlighting the contributions ofveterinary scientists to this area of study. Such examples illustrate the need forcommunication and collaboration between the veterinary and medicalcommunities to understand and control emerging zoonotic diseases of the 21st Century.

KeywordsAnimal coronavirus – Enteric and respiratory coronavirus – Severe acute respiratorysyndrome – Zoonosis.

Introduction and chronology of severe acute respiratorysyndromeSevere acute respiratory syndrome (SARS) emerged inGuangdong Province, the People’s Republic of China, in2002 and within months, spread globally. A clinically illphysician from the People’s Republic of China sparked asuper-spreading event at the Metropole Hotel in HongKong in February 2003. This episode triggered the spread

of SARS to Vietnam, Singapore and Canada, therebyaffecting both developing countries lacking a good publichealth infrastructure and developed countries with modernpublic health systems. The rapid global spread of a newdisease of unknown aetiology with no available diagnostictests or treatments resulted in the World Health

Organization (WHO) issuing the most stringent traveladvisory in its history in March 2003 (53).

Lacking the research and investigative capacity to controlthe epidemic, the WHO elicited public health servicepartners from countries such as the United States ofAmerica (USA) (52), the United Kingdom, theNetherlands, Germany and France. The Global Alert andResponse Network of the WHO, which includes a virtualnetwork of eleven leading and well-equipped infectiousdisease laboratories in nine countries, previouslyestablished to address mainly influenza outbreaks, wasinstrumental in spearheading laboratory efforts (53). Theselaboratories were connected by secure websites andteleconferences to identify the causative agent of SARS,develop diagnostic tests and collect and analyse clinicaland epidemiological data on the disease. Similarly, the USA Centers for Disease Control and Prevention (CDC)established other virtual interdisciplinary teams in theUSA, eliciting help from both medical and veterinarycoronavirus (CoV) experts (52). Both the WHO and theUSA CDC provided factual information on SARS throughupdated websites, hotlines and frequent presentations tothe news media to educate the public.

In spite of recent rapid advances in molecular virology andbiotechnology, classical virology methods (electronmicroscopy, cell culture isolation, immunofluorescence)were instrumental in first identifying this unknown agentas a CoV, in adapting the organism to cell culture and thenin developing initial assays for its detection and forantibody detection (47, 65, 66). Thus, exceptionalinternational laboratory efforts led to the rapid geneticsequencing and identification of a new CoV as thecausative agent of SARS by April 2003, only about onemonth after the initial WHO global alert (18, 47, 55, 66,68, 69). Although vaccines or antivirals to prevent orcontrol SARS infections were lacking, the epidemic wascountered by classical infection control and containmentmethods. On 5 July 2003, the WHO reported that theglobal SARS epidemic was contained after over 8,000 casesand about 800 deaths in 29 countries. However, since thenand into 2004, new cases of SARS have emergedsporadically in Singapore, Taiwan and the People’s Republic of China, most of which were associatedwith laboratory-acquired exposure to the disease. Thesecases did not spread by contact, with the exception of themost recent cases (March/April 2004) from the People’sRepublic of China in which multiple contacts were infectedand at least one died. The laboratory-acquired exposure toSARS CoV demonstrates that adherence to the strictlaboratory safety procedures required for work withBiosafety Level 3 (BSL-3) pathogens is vital. Thewidespread distribution of SARS CoV samples ininternational laboratories highlights the need for vigilancein the inventory and use of these virus stocks. In addition,adequate laboratory supervision and facilities are required

to avoid future laboratory-acquired infections as a possiblesource of a new SARS epidemic.

In summary, the unprecedented SARS super-spreadingevents precipitated the transmission of the disease, evenwithin modern, well-equipped hospital environments (79),secondarily infecting and incapacitating health careworkers and compromising the health care system.International air travel also facilitated the rapid worldwidespread of the disease (64, 100), thereby contributing to theglobal SARS epidemic. Countries such as Vietnam, whichrapidly implemented and enforced control measures andsought international guidance, were able to effectivelycontain the epidemic. Other countries with delayedresponses or a lack of transparency in reporting diseasecases, such as the People’s Republic of China, experienceda more devastating and widespread epidemic (41). Finally,implementation of effective surveillance and controlmeasures, definitive identification of the causative agent ofSARS as a CoV and containment of the epidemic canlargely be attributed to an unparalleled level of global co-operation in combating the newly emerged global disease.

The origin of severe acuterespiratory syndrome: is severeacute respiratory syndrome a zoonosis?

Wildlife reservoirsApproximately 75% of emerging infectious diseases are ofzoonotic origin (87). Epidemiological and genetic datahave been presented postulating that SARS evolved from awild animal host, but no definitive evidence yet exists toprove this hypothesis. Epidemiological observationssupporting the theory include the following: the indexpatient in Guangxi Province was a wild animal trader, twoof seven index patients were restaurant chefs, foodhandlers were over-represented in early-onset cases withno contact history and early-onset patients were morelikely to live near agricultural live animal markets (but noton or near farms) (101). This temporal and spatialclustering of index cases is consistent with the classicalemergence of new agents from animal reservoirs.

Based on genetic and antigenic analysis, CoVs isolatedfrom two clinically normal wild animal species (Himalayan palm civets, also referred to as masked palmcivets or civet cats [Paguma larvata] and a raccoon dog [Neyctereutes procyonoides]) from wild animal markets inShenzen, the People’s Republic of China, have beenassigned as members of the new SARS CoV group (24). All

Rev. sci. tech. Off. int. Epiz.,23 (2)644

Rev. sci. tech. Off. int. Epiz., 23 (2) 645

the animal SARS CoV isolates possessed a 29 nucleotidesequence not found in most human isolates. Furthermore,the highest IgG antibody titres to SARS CoV were observedin traders of masked palm civets (72.7%) compared totraders of all live animals (13%) and healthy controls(1.2%) (8). However, the reservoir for SARS is stillunknown and whether civet cats transmitted SARS CoV tohumans or vice versa is undefined. Nevertheless, these datashow that live animal markets (wet markets), which notonly exist in the People’s Republic of China but throughoutthe world, are likely to have played a pivotal role in theemergence of SARS CoV. These live markets areacknowledged as breeding grounds for influenza virusoutbreaks such as that which occurred in Hong Kong inFebruary 2003. The unsanitary crowded conditions, co-mingling of or close contact among different species ofanimals and between animals and humans, the carryoverof animals and the introduction of new animals and animalslaughter on the premises, with the dispersion of bloodand secretions or offal, all foster an environment conduciveto the emergence of new zoonotic diseases.

To date, only animals (mainly wild animals) in the SARSendemic areas have been tested for SARS CoV orantibodies; animals outside the endemic regions have notbeen tested. In addition, unless more stringent, butcumbersome (requiring BSL-3 facilities) virusneutralisation tests are conducted to confirm antibodyseroprevalence in humans and animals, the results usingintact SARS CoV or nucleocapsid (N) protein may besuspect. This is because of the documented antigeniccross-reactivity (enzyme-linked immunosorbent assay[ELISA], Western blots, immunofluorescence) observedbetween SARS CoV and animal group I CoVs (47)attributed to the N protein (26, 85). These issues hinderdefinitive analysis of animal reservoirs for SARS.

Between December 2003 and January 2004, several newcases of SARS re-emerged in humans in GuangdongProvince, the People’s Republic of China (61). In most ofthese cases there was no link to known risk factors such ascivet cats. Other postulated reservoirs including rats andcats were tested, but no final conclusions were drawnconcerning the origin of this re-emergent case. However,based on sequence data suggesting that the re-emergedSARS strains were most similar to the civet cat isolates(61), the Government of the country ordered thedestruction of large numbers of civet cats in the wildlifemarkets in the People’s Republic of China (98).

Other animal hosts or vectors for severe acuterespiratory syndrome coronavirusIn addition to the Metropole Hotel outbreak, a secondmajor outbreak of SARS occurred in 2003 in anotherlocation in Hong Kong at the Amoy Gardens apartments

where 321 people were ultimately infected (9). Thisoutbreak was clinically more severe and associated withmore cases of diarrhoea (73%), higher intensive care unitadmissions (32%) and mortality rates (13%) than theMetropole Hotel outbreak. Environmental factors (faultysewage system) were postulated to have contributed tovirus spread in the Amoy Gardens via aerosolised faecalmaterial (39). However, an alternative hypothesis proposedwas that an animal vector, such as roof rats, infected by theindex patient, rapidly spread the disease among the 150affected households (59). The authors further speculatedthat dual infections of rats with a rat CoV and SARS CoVmay have been required to cause a productive SARS CoVinfection in other rats. Indeed, CoV was detected in rodentdroppings from the apartment complex, but since therodents showed no disease, they were postulated to bemechanical viral vectors (39). It is also interesting to notethat virus remnants were detected from throat or rectalswabs of five house cats, one of which had antibodiesreactive with SARS CoV (59).

These data are consistent with SARS animal transmissionstudies which revealed that the respiratory tract of both miceand cats can be experimentally infected with SARS CoV,although infections in both species remained sub-clinical (56, 84). Moreover, both experimentally-infectedcats and ferrets (Mustelo furo) transmitted virus to theircontact-exposed cage mates (56). In the experimental animaltransmission studies performed to date, only cynomologusmacaques (Macaca cynomologus) (in some studies, but notothers) and ferrets have been reported to develop variabledisease expression after infection by SARS CoV, with SARSCoV shedding detected from nasal or pharyngeal swabs (22,56). However, in neither species do the clinical signscompletely mirror those of human SARS cases, which includethe delayed onset of clinical disease and frequent diarrhoeawith CoV shedding in stools (9, 47, 65, 68).

Attempts have been made to experimentally transmit SARSCoV to domestic livestock and poultry. Weingartl et al. (99)reported failure to transmit SARS CoV to six-week-old pigsthat were seropositive for antibodies to porcine respiratoryCoV (PRCV) (a group I animal CoV). However, the authorsdetected SARS CoV ribonucleic acid (RNA) in the blood byreverse transcriptase-polymerase chain reaction (RT-PCR)and noted that the pigs seroconverted with neutralisingantibodies to SARS CoV. This study should be repeated inpigs seronegative for PRCV or other CoV antibodiesbecause several investigators have noted that antibodies toPRCV and other animal group I CoVs cross-react withSARS CoV (26, 47, 85). Whether such pre-existingantibodies to group I CoV interfere with SARS CoVinfection is unclear. Both Weingartl et al. (99) and Swayneet al. (86) also reported lack of SARS CoV transmission tospecific pathogen-free chickens, turkeys, ducks or quail,although again some RT-PCR positive samples weredetected among the exposed poultry.


Classification and evolution of severe acute respiratorysyndrome and animalcoronavirusesWithin months of the emergence and global spread ofSARS, the causative agent was identified as a new CoV, onlydistantly related to known CoVs of humans or animals (18,47, 55, 66, 68, 69). The existing animal CoVs comprisethree groups based on high levels of antigenic or geneticrelatedness of species within a group and lower relatednessamong CoV species of the different groups (Table I). TheSARS CoV and two wild animal SARS-like CoVs (24) havebeen tentatively assigned to group IV (Table I), based onphylogenetic analysis (18, 47, 55, 66, 68, 69).Alternatively, SARS CoVs may comprise a subgroup ofgroup II CoVs based on rooted tree phylogenetic analysis(78). Additional phylogenetic analysis suggests that SARSCoV may have evolved from a distant recombination event

between ancestral mammalian-like and avian-like parentalCoV strains (80).

Although CoVs generally do not cross-react antigenicallyacross groups, an interesting but unexplained observationis the cross-reactivity between several animal members ofgroup I CoVs (transmissible gastroenteritis virus [TGEV],PRCV, feline infectious peritonitis virus [FIPV], caninecoronavirus [CaCoV]) and SARS CoV (47), probably at theinner N protein level (26, 85). This suggests that althoughthe genetic divergence between SARS CoV and other CoVsis high, a conserved epitope on the N protein may exist.

The emergence of SARS in healthy adults surprised themedical community, but veterinary coronavirologists havelong recognised the potential of CoVs to produce lethalinfections in young animals. Coronaviruses cause a broadspectrum of diseases in domestic and wild animals, poultryand rodents ranging from mild to severe enteric,respiratory or systemic disease, as well as minor colds inhumans (7, 14, 15, 48, 51, 67, 70, 71, 72, 73, 74) (TableI). In livestock and poultry, CoVs cause mainly localised

Table IAnimal coronaviruses: groups, target tissues and types of diseases

Disease/Infected tissue Respiratory Enteric Other

I Human coronavirus-229E Human x(a) (upper)

Transmissible gastrointestinal virus Pig x (upper) x (SI) Viraemia

Porcine respiratory coronavirus Pig x (upper/lower)

Porcine epidemic diarrhoea virus Pig x (SI, colon)

Feline enteric coronavirus Cat x

Feline infectious peritonitis virus Cat x (upper) x (SI) Systemic

Canine coronavirus Dog x (SI)

Rabbit coronavirus Rabbit Systemic

II Human coronavirus-OC43 Human x (upper) BCoV?(b)

Mouse hepatitis virus Mouse x Liver, CNS, systemic

Rat coronavirus (sialodocryadenitis) Rat x Eye, salivary glands

Haemagglutinating encephalitis virus Pig x CNS

Bovine coronavirus Cattle x (upper, lung) x (SI, colon)

III Infectious bronchitis virus Chicken x (upper) x (no diarrhoea) Viraemia, kidney, oviduct

Turkey coronavirus Turkey x (SI)

IV? Severe acute respiratory syndrome Human x (lung) x? Viraemia, kidney?

Civet cat coronavirus Himalayan palm civet x x Sub-clinical?

Raccoon dog coronavirus Raccoon dog ? x Sub-clinical?

a) if no specific information is provided in parentheses, the entire respiratory/gastrointestinal tract is affected or the specific site of infection is not knownb) bovine coronavirus-like coronavirus from a child (102)SI: small intestine?: unknown or unreportedCNS: central nervous system

Virus HostGeneticgroup

enteric or respiratory infections, although infectiousbronchitis virus (IBV) of poultry causes both upperrespiratory and systemic infections targeting the kidney(interstitial nephritis) and oviduct (decreased eggproduction) (7, 15). Coronaviruses are enveloped andpossess four major proteins, i.e. the nucleocapsid (N) proteinsurrounding the RNA genome and three membrane proteins:the surface spike (S) glycoprotein, the membrane (M)glycoprotein and the envelope (E) protein (48). In addition,some group II CoVs can be distinguished from other CoVsby a surface haemagglutinin (HE), apparent as a shorter layerof projections on the virion surface compared to the longer Sprojections. Typical group I CoV particles (TGEV) thatclearly display the surface S protein spikes are shown in theimmune electron micrograph in Figure 1a, while Figure 1bpresents group II CoV particles (bovine CoV [BCoV])displaying the dense outer surface projections consisting ofboth the longer spike and shorter HE proteins. The S proteinappears to be a critical determinant for viral attachment andfusion, cell tropism, species specificity, pathogenicity andinduction of neutralising antibodies (1, 58, 75). The CoVgenome consists of linear, single-stranded RNA of positivepolarity and ranges from 28 kb-32 kb in length (48). ForCoVs, the large size of the RNA genome, the replicationstrategy (nested set of sub-genomic RNAs) and the lack ofproof-reading enzymes for RNA replication (analogous toother RNA viruses), all contribute to the recognisedpropensity of CoVs to recombine or mutate and for newstrains to emerge.

Numerous examples illustrate the emergence of newanimal CoV strains or the mutation of existing strains toproduce natural variants or host range mutants. In the late1970s and into the 1980s, a new group I porcine CoV, theporcine epidemic diarrhoea CoV (PEDV), appeared inEurope and rapidly spread to Asia (67). The diseaseresembled TGEV of swine and caused severe diarrhoeawith major losses of piglets, before becoming enzootic inswine. The disease is still absent from the USA. It isinteresting to note that PEDV is genetically more similar tohuman CoV-229E (229E) than to the other animal group ICoVs (19) and antibodies to PEDV fail to neutralise TGEVor PRCV, although a shared antigen in Western blot isreported (67). Unlike other group I CoVs, but like SARSCoV (47, 65), PEDV grows in Vero cells (38), which raisesintriguing questions about the origin of the disease.

Alternatively, new CoV strains with altered tissue tropismsand virulence may also arise from existing strains. Forexample, the less virulent PRCV evolved as an S genedeletion mutant of the highly virulent TGEV (TGEV-V)(51, 74). Size differences in the 5’ end S gene deletionregion (621-681 nucleotides) of European versusAmerican strains of PRCV support their independentorigin on two continents within a similar time-frame(1980s). Deletion of this region (or in combination withdeletions in open reading frame 3a) presumably accountedfor altered tissue tropism from enteric to respiratory andreduced virulence of the PRCV strains (1).


a) Group I coronavirus particles (transmissible gastroenteritis virus) with the surface spike protein clearly visible (arrow)b) Group II coronavirus particles (bovine coronavirus) displaying the dense outer surface projections consisting of longer spikes (arrow) and shorter haemagglutinin (arrowhead)

Fig. 1Electron micrograph showing immune electron microscopy of coronavirus particlesCoronaviruses were incubated with diluted hyperimmune antiserum to the respective coronavirus

100 nm

a100 nm

b


Another example of an animal CoV that has evolved withaltered tissue tropism and virulence from the less virulentfeline enteric CoV (FCoV) (37, 97) is FIPV, a virulentsystemic variant, which probably evolved as a persistentinfection of cats with FCoV. This ability of certain CoVs topersist in their host also provides a longer opportunity fornew mutants to be selected with altered tissue tropismsand virulence from among the viral RNA quasispecies (orswarm of viruses).

In addition, animal CoVs may acquire new genes viarecombination, as demonstrated by the acquisition of aninfluenza C-like HE by BCoV or an ancestoral CoV (2).Recombination among CoVs may also generate new strainswith altered tissue or host tropisms. Experimental targetedrecombination between feline and mouse S protein genesenables FCoV to infect mice (27). Recent phylogeneticanalysis suggests that SARS CoV may have evolved from adistant past recombination event between mammalian-likeand avian-like parent strains, with the S gene representing amammalian (group I)-avian (group III) origin mosaic (80).This recognition that CoVs can further evolve in a hostpopulation to acquire new tissue tropisms or virulence viamutations or recombination suggests that similar events mayoccur if SARS CoV infections persist in humans.

Interspecies transmission ofcoronavirusesThe likelihood that SARS CoV is a zoonotic infectionpotentially transmitted from wild animals to humans is notunprecedented based on previous veterinary research oninterspecies transmission of animal CoVs and wildlifereservoirs for CoV. For example, the group I porcine CoV(TGEV and PRCV), CaCoV and FCoV are antigenically andgenetically closely related CoVs that appear to be hostrange mutants of an ancestral CoV (40, 57, 74). Theycross-infect pigs, dogs and cats with variable diseaseexpression and levels of cross-protection in theheterologous host (73, 74). Wildlife reservoirs for CoVswere recognised prior to SARS. Wild and domesticcarnivores (foxes [Vulpes vulpes], dogs and possibly mink[Mustela vison]) seroconvert to TGEV and are suggested aspotential sub-clinical carriers of TGEV, serving as reservoirsbetween seasonal (winter) epidemics, although only virusexcreted by dogs was infectious for pigs (74). Serologicalevidence for a CoV cross-reactive with TGEV was reportedin minks (33). Wild birds (Sturnus vulgaris) and flies(Musca domestica) have been proposed as mechanicalvectors for TGEV (74).

Captive wild ruminants from the USA including Sambardeer (Cervus unicolor), white-tailed deer (Odocoileusvirginianus), waterbuck (Kobus ellipsiprymnus) and

elk/wapiti (Cervus elaphus) harbour CoVs antigenically(cross-neutralising) closely related to BCoV (54, 89). Thedeer and waterbuck isolates were from animals withbloody diarrhoea resembling winter dysentery (WD) incattle (89). They infected and caused diarrhoea inoronasally-inoculated gnotobiotic calves, therebydemonstrating that wild ruminants may serve as a reservoirfor CoV strains transmissible to cattle. Unfortunately, theseCoVs have not been sequenced to assess their geneticsimilarity to BCoV.

The promiscuousness of BCoV is evident by infection of dogsand humans by genetically similar (> 97% nt identity) CoVstrains (21, 102). Bovine CoV can also experimentally infectand cause disease (diarrhoea) in phylogenetically diversespecies such as avian hosts including baby turkeys, but notbaby chicks (43). The latter study notably showed thatBCoV-infected baby turkeys also transmitted the viruses tounexposed contact control birds. These data raise intriguingquestions such as whether wild birds (e.g. wild turkeys)could also be a reservoir for CoVs transmissible to cattle orconversely, whether cattle (or ruminants) can transmit CoVsto wild birds or poultry. The reasons for the broad host rangeof BCoVs are unknown, but may be related to the presenceof an HE on BCoV and the possible role of the protein inbinding to diverse cell types.

Recent data suggest that SARS CoV may also have a broadhost range in addition to humans. Genetically similar CoVswere isolated from civet cats and racoon dogs (24).Experimental infection with the SARS CoV caused clinicaldisease in macaques and ferrets and sub-clinical infectionin cats (22, 56). In the latter two species, the SARS CoVwas further transmitted to exposed contacts,demonstrating transmission within a new host species.Consequently, although previous data document theemergence of new animal CoV strains and the broad hostrange of several CoVs, the determinants for host rangespecificity among CoVs are undefined. In addition, little isunderstood about CoVs circulating in wildlife andrelatively few animal CoV strains have been fullysequenced for comparative phylogenetic analysis to tracetheir evolutionary origins.

Pathogenesis of enteric andrespiratory coronaviruses inlivestock and poultryGiven that both pneumonia and diarrhoea occur in SARSpatients, an understanding of the tissue tropisms andpathogenesis of respiratory and enteric animal CoVsshould contribute to the understanding of similarparameters for SARS. Veterinary research on respiratory

and enteric CoV infections in the natural animal host(swine, cattle, poultry) has provided importantinformation on CoV disease pathogenesis, possiblepotentiators for increased disease severity and vaccinestrategies potentially applicable to SARS CoV. Enteric CoVinfections alone frequently cause fatal infections in younganimals (73, 74). A notable difference between SARS CoVand most fatal animal CoV infections is the unexplainedpropensity of SARS to cause more severe disease in adultsthan children. However, in adult animals, respiratory CoVinfections are more severe or often fatal when combinedwith other factors including stress and transport of animals(shipping fever of cattle), high exposure doses, aerosols,treatment with corticosteroids and other respiratory co-infections (viruses, bacteria, bacterial lipolysaccharides).Similarly, such variables may influence the severity of SARSor contribute to the phenomenon of super-spreading of thedisease. The following sections provide a perspective onthe pathogenesis of selected group I, II and III enteric andrespiratory CoV infections of livestock and poultry and therole of the various above co-factors in disease potentiation.

Group I transmissible gastroenteritis virus and porcine respiratory coronaviruses:comparative pathogenesis of enteric and respiratory infectionsThe emergence in the 1980s of a naturally occurring S genedeletion mutant of TGEV with an altered tissue tropism,the PRCV, provided a unique opportunity for comparativestudies of these two CoVs in the same host species (pigs).Transmissible gastroenteritis virus and PRCV exemplifylocalised enteric (TGEV) or respiratory (PRCV) infectionsmost severe in neonatal (less than two weeks) or youngadult (one to three months) pigs, respectively (51, 74).Transmissible gastroenteritis virus targets small intestinalepithelial cells, leading to severe villous atrophy,malabsorptive diarrhoea and potentially fatalgastroenteritis (Table I). The virus also infects the upperrespiratory tract with transient nasal shedding (95), butinfection or lesions in the lung are less common. In adults,TGEV is mild with transient diarrhoea or inappetence, butpregnant or lactating animals develop more severe clinicalsigns and agalactia (74).

Porcine respiratory coronavirus, an S gene deletion mutant ofTGEV, presents altered tissue tropism (respiratory) andreduced virulence (51, 74). Like SARS, PRCV spreads bydroplets and has a pronounced tropism for the lung,replicating to titres of 107-108 tissue cell infective dose(TCID)50 and producing interstitial pneumonia affecting from5% to as high as 60% of the lung (17, 28, 34, 51, 74).Although many uncomplicated PRCV infections are mild orsub-clinical, lung lesions are almost invariably present. LikeSARS, clinical signs of PRCV include fever with variabledegrees of dyspnea, polypnea, anorexia and lethargy, and

some coughing and rhinitis (17, 28, 34, 51, 74). Furtherresembling SARS (13, 60), PRCV replicates in lung epithelialcells and antigen is detected in type I and II pneumocytesand alveolar macrophages. In the lungs, bronchiolarinfiltration of mononuclear cells, lymphohistiocytic exudatesand epithelial cell necrosis leads to interstitial pneumonia.Like SARS, porcine respiratory CoV induces transientviraemia with virus also detected from nasal swabs and in thetonsils and trachea (18, 47, 65). The disease furtherreplicates in undefined cells in the intestinal lamina propria,but without inducing villous atrophy or diarrhoea and withlimited faecal shedding (17, 28, 34, 74). Recently however,faecal isolates of PRCV were detected with consistent, minor(point mutations) changes in the S gene compared to nasalisolates from the same pig (16). No diarrhoea and limitedfaecal shedding were observed in pigs inoculated with thefaecal PRCV isolates, suggesting their possible lack ofintestinal stability. Such observations suggest the presence ofCoV quasispecies in the host with some strains more adaptedto the intestine, a potential corollary for the faecal sheddingof SARS CoV (9, 18, 47, 65). Of further relevance to SARS,was the displacement of the TGEV-V infections bywidespread dissemination of the clinically milder PRCV inEurope and the disappearance of PRCV from swine herds insummer with re-emergence of the disease in older pigs inwinter (51, 74).

The emergence of PRCV also permitted comparativeimmunological studies of the immune responses andprotection to the enteric TGEV versus the respiratory PRCVin the porcine host. Both passive immunity targetingmaternal vaccination to provide passive antibodies in milk tosuckling pigs and active immunity have been evaluated forthe two CoVs. VanCott et al. (95, 96) and Brim et al. (3, 4)compared B cell (antibody-secreting cells [ASC]) and T cell(lymphoproliferative [LP] responses) immune responses toTGEV-V and PRCV in young pigs to assess theinterrelationships among components of the commonmucosal immune system (gut-associated lymphoid tissue[GALT] and bronchus-associated lymphoid tissue [BALT])and induction of protective immunity to TGEV challenge.Only TGEV-V primed for high numbers of IgA ASC and LPresponses in the intestine (GALT) and induced almostcomplete protection against TGEV challenge. A single PRCVinfection of the respiratory tract (BALT) induced few IgAASC and low LP responses in the intestine, but highernumbers of IgG ASC and higher LP responses in the lowerrespiratory tract (bronchial lymph nodes). Importantly,PRCV infection primed for anamnestic IgG and IgA intestinalantibody responses after TGEV challenge, leading to partialprotection against diarrhoea and virus shedding. Similarly, asingle infection of the respiratory tract of pregnant swinewith PRCV induced only partial passive immunity to TGEV(5, 74), but interestingly, repeated PRCV infections of themother induced higher IgA antibody responses in milk andprotection rates to TGEV (76). This finding suggests thatrepeated PRCV exposure is needed to stimulate adequate


numbers of IgA memory cells in the intestine for subsequenttransit to the mammary gland and secretion of protectivelevels of IgA antibodies in milk. These data show thatcompartmentalisation exists within the common immunesystem whereby stimulation at one mucosal site does notnecessarily evoke complete reciprocity in immune responsesor protection at other distant mucosal sites. The analogy toSARS is that respiratory vaccines for SARS may notcompletely prevent the diarrhoeal disease or faecal sheddingif, like TGEV, SARS CoV also infects the intestine, therebypermitting the continued circulation of SARS CoV in apopulation.

Group II bovine coronavirus: pneumoentericinfectionsThe shedding of SARS in the faeces of many patients andthe occurrence of diarrhoea in 10% to 27% of patients(65), but with a higher percentage (73%) in the AmoyGardens, Hong Kong outbreak (9) suggest that SARS maybe pneumoenteric like BCoV. Bovine coronavirus causesthree distinct clinical syndromes in cattle (73), i.e. calfdiarrhoea (14, 73), WD with haemorrhagic diarrhoea inadults (70, 88, 90, 91) and respiratory infections in cattleof various ages including cattle with shipping fever (TableI) (10, 14, 29, 30, 31, 32, 35, 36, 49, 50, 73, 81, 82, 83).The virus is ubiquitous in cattle worldwide based on BCoVantibody seroprevalence data. All BCoV isolates from bothenteric and respiratory infections are antigenically similar,comprising a single serotype, but with two to threesubtypes identified by neutralisation tests or usingmonoclonal antibodies (14, 29, 30, 73, 90). In addition,genetic differences (point mutations but not deletions)have been detected in the S gene, differentiating betweenenteric and respiratory isolates, including those from thesame animal (12, 32). Nevertheless, inoculation ofgnotobiotic or colostrum-deprived calves with calfdiarrhoea, WD or respiratory BCoV strains led to bothnasal and faecal CoV shedding and cross-protection againstdiarrhoea after challenge with a calf diarrhoea strain (11,20). However, sub-clinical nasal and faecal virus sheddingdetected in calves challenged with the heterologous BCoVstrains (11, 20) confirmed field studies showing that sub-clinically infected animals may be a reservoir for BCoV (35,36). Cross-protection against BCoV-induced respiratorydisease has not been evaluated.

Calf diarrhoea and calf respiratory bovinecoronavirus infections

Calves under three weeks of age infected with BCoVdevelop a severe, malabsorptive diarrhoea resulting indehydration and often death (14, 73). Concurrent faecaland nasal shedding often occurs. Calf diarrhoea BCoVstrains infect the epithelial cells of the distal small and largeintestine and superficial and crypt enterocytes of the colon,

leading to villous atrophy and crypt hyperplasia (73, 92).Bovine coronavirus is also implicated as a cause of mildrespiratory disease (coughing, rhinitis) or pneumonia intwo to twenty-four-month-old calves and is detected innasal secretions, the lungs and often the intestines andfaeces (14, 35, 36, 73). In studies of calves from birth totwenty weeks of age, Heckert et al. (35, 36) documentedboth faecal and nasal shedding of BCoV, with repeatedrespiratory shedding episodes in the same animal, with orwithout respiratory disease, and subsequent transientincreases in their serum antibody titres consistent withthese re-infections. These findings suggest a lack of long-term mucosal immunity in the upper respiratory tract afternatural CoV infection, confirming similar observations forhuman respiratory CoV (6) and PRCV (5).

Winter dysentery bovine coronavirus infections

Winter dysentery occurs in captive wild ruminants (89)and adult cattle during the winter months and ischaracterised by haemorrhagic diarrhoea, frequentrespiratory signs and a marked reduction in milkproduction in dairy cattle (70, 73, 92). Intestinal lesionsand BCoV-infected cells in the colonic crypts resemblethose described for calf diarrhoea (92). The BCoV isolatesfrom WD outbreaks at least partially reproduced thedisease in BCoV seropositive non-lactating cows (91) andin BCoV seronegative lactating cows (88). Interestingly, inthe later study, the older cattle were more severely affectedthan similarly exposed calves, mimicking the more severeSARS cases observed in adults compared to children (45).

Shipping fever bovine coronavirus infections

Since 1995, BCoVs have been associated with respiratorydisease (shipping fever) in feedlot cattle (49, 50, 81).Bovine coronavirus was isolated from nasal secretions andlungs of cattle with pneumonia and from faeces (29, 30,31, 49, 50, 81, 82, 83). In a subsequent study, a highpercentage of feedlot cattle (45%) shed BCoV both nasallyand in faeces as evidenced by ELISA (10). Application ofnested RT-PCR detected higher BCoV nasal and faecalshedding rates of 84% and 96%, respectively (31). Co-factors contributing to the severity of shipping fever arediscussed in the subsequent sections.

Group III infectious bronchitis virus: upperrespiratory coronavirus infection with othertissue targetsInfectious bronchitis is a highly contagious respiratoryviral disease of chickens, which, like SARS, is spread byaerosol or possibly faecal-oral transmission and distributedworldwide (7, 15). Genetically and antigenically closelyrelated CoVs have been isolated from pheasants andturkeys (25, 42), but in young turkeys, they mainly causeenteritis. Respiratory infections of chickens are


characterised by tracheal rales, coughing and sneezing,with the disease most severe in chicks (7, 15). Infectiousbronchitis virus also replicates in the oviduct, causingdecreased egg production. Nephropathogenic strains cancause mortality in young birds. Infectious bronchitis virusis recovered intermittently from the respiratory tract forabout 28 days after infection and from the faeces afterclinical recovery, with the cecal tonsil being a possiblereservoir for IBV persistence in the same way as theintestines of cats are a reservoir for the persistence of FCoV(37). Infectious bronchitis virus was recovered from bothtracheal and cloacal swabs in chickens at onset of eggproduction, suggesting re-excretion of IBV fromchronically infected birds, as also demonstrated for faecalshedding of FCoV or BCoV after induction ofimmunosuppression (62, 63, 91).

Infectious bronchitis virus replicates in epithelial cells ofthe trachea and bronchi, intestinal tract, oviduct andkidney causing necrosis and oedema with small areas ofpneumonia near large bronchi in the respiratory tract andinterstitial nephritis in the kidney (7, 15). Of interest forSARS, is the persistence of IBV in the kidney and theprolonged faecal shedding of the virus, because SARS CoVis detected in the urine and shed for longer in the faeces.However, it is unclear whether SARS CoV shedding inurine is a consequence of viraemia or a kidney infectionlike IBV. Both diagnosis and control of IBV are complicatedby the existence of multiple serotypes and the occurrenceof IBV recombinants (7, 15). This is unlike the scenario formost group I or II respiratory CoVs in which only 1 or 2(FCoV) serotypes are known. Also relevant to SARS CoV isthe finding that IBV strains also replicate in Vero cells, butonly after passage in chicken embryo kidney cells (7).

Co-factors that exacerbatecoronavirus infections, diseaseor sheddingUnderlying disease or respiratory co-infections, dose androute of infection and immunosuppression(corticosteroids) are all potential co-factors related to theseverity of SARS. These co-factors can also exacerbate theseverity of BCoV, TGEV or PRCV infections. Additionally,they may also play a role in the super-spreader casesobserved with the SARS epidemic (46) by enhancing virustransmission or host susceptibility.

Impact of respiratory co-infections oncoronavirus infections, disease and sheddingShipping fever is recognised as a multifactorial,polymicrobial respiratory disease complex in young adult

feedlot cattle with several factors exacerbating respiratorydisease, including BCoV infections (49, 50, 81, 82, 83).The disease can be precipitated by several viruses, alone orin combination (BCoV, bovine respiratory syncytial virus[RSV], parainfluenza-3 virus, bovine herpesvirus),including viruses similar to common human respiratoryviruses and viruses capable of mediatingimmunosuppression (bovine viral diarrhoea virus, etc.).The shipping of cattle over long distances to feedlots andthe co-mingling of cattle from multiple farms createphysical stresses that overwhelm the defence mechanismsof the animals and provide close contact for exposure tohigh concentrations of new pathogens or strains notpreviously encountered. Such factors are analogous to thephysical stress of long aeroplane trips with close contactamong individuals from diverse regions of the world, bothof which may play a role in enhancing the susceptibility oftravellers to SARS or the transmission of SARS (64, 100).For shipping fever, various predisposing factors (viruses,stress) enable commensal bacteria of the nasal cavity(Mannheimia haemolytica, Pasteurella sp., Mycoplasma sp.,etc.) to infect the lungs, leading to fatal fibrinouspneumonia (49, 50, 81, 82, 83) such as that seen in SARSpatients (13, 60, 65). In broiler chickens, severe disease ordeath ensues from systemic Escherichia coli co-infectionsafter IBV damage to the respiratory tract or Mycoplasma sp.co-infections with IBV (15).

Antibiotic treatment of such animals (or SARS patients) co-infected with CoVs and bacteria, with the massive release ofbacterial lipopolysaccharides (LPS), may precipitateinduction of pro-inflammatory cytokines, which may furtherenhance lung damage. For example, Van Reeth et al. (94)showed that pigs infected with PRCV then given a sub-clinical dose of E. coli LPS within 24 h developed enhancedfever and more severe respiratory disease compared toanimals infected with each agent alone. They concluded thatthe effects were probably mediated by the significantlyenhanced levels of pro-inflammatory cytokines induced bythe bacterial LPS. Therefore, both LPS and lung cytokinelevels need to be examined in SARS patients as possiblemediators of the severity of SARS. Bacteria (Chlamydia sp.)have been isolated from SARS patients, but their role inenhancing the severity of SARS is undefined (68).

Interactions between PRCV and other respiratory virusesmay also parallel the potential for concurrent or pre-existing respiratory viral infections to interact with SARSCoV (such as metapneumoviruses, influenza, reoviruses,RSV, human coronavirus-OC43 [OC43] or 229E). Hayes(34) showed that sequential dual infections of pigs with thearterivirus porcine respiratory reproductive syndrome(PRRSV) (order Nidovirales, like CoV), followed ten dayslater by PRCV, significantly enhanced lung lesions andreduced weight gains compared to animals infected witheach virus alone. The dual infections also resulted in morepigs shedding PRCV nasally for a prolonged period and


surprisingly, to faecal shedding of PRCV. The lung lesionsobserved resembled those in SARS victims (13, 60).

In another study, Van Reeth and Pensaert (93) inoculatedpigs with PRCV then two to three days later, with swineinfluenza A virus (SIV). They found that SIV lung titreswere reduced in the dually- compared to the singly-infected pigs, but paradoxically, the lung lesions were moresevere in the dually-infected pigs. They postulated that thehigh levels of interferon (IFN)-alpha induced by PRCVmay mediate interference with SIV replication, but mightalso contribute to enhanced lung lesions. Such studies arehighly relevant for possible dual infections by SARS CoVand influenza virus and for the potential treatment of SARSpatients with IFN-alpha.

Impact of route (aerosols) and dose oncoronavirus infectionsExperimental inoculation of pigs with PRCV strainsshowed that administration of PRCV by aerosol comparedto the oronasal route, or in higher doses, resulted in highervirus titres shed and longer shedding (95). In otherstudies, high PRCV doses induced more severe respiratorydisease. Pigs given 108.5 TCID50 of PRCV developed moresevere pneumonia and more deaths were observed than inpigs exposed by contact (44). Furthermore, higherintranasal doses of another PRCV strain (AR310) inducedmoderate respiratory disease whereas lower dosesproduced sub-clinical infections (28). By analogy, hospitalprocedures that could potentially generate aerosols, orexposure to higher initial doses of SARS CoV may enhanceSARS transmission or lead to enhanced respiratory disease(46, 79).

Impact of treatment with corticosteroids oncoronavirus infections of animalsCorticosteroids are known to induce immunosuppressionand reduce the numbers of cluster of differentiationantigen (CD) 4 and CD 8 T cells and certain cytokine levels(23). Many hospitalised SARS patients were treated withsteroids to reduce lung inflammation, but there are no datato assess the outcome of this treatment on virus sheddingor respiratory disease. A recrudescence of BCoV faecalshedding was observed in one of four WD BCoV-infectedcows treated with dexamethasone (91). Similarly,treatment of older pigs with dexamethasone prior to TGEVchallenge led to profuse diarrhoea and reduced LPresponses in the treated pigs (77). These data raise issuesfor corticosteroid treatment of SARS patients related topossible transient immunosuppression, resulting inenhanced respiratory disease or increased and prolongedCoV shedding (super-spreaders). Alternatively,corticosteroid treatment may be beneficial in reducing pro-

inflammatory cytokines if found to play a major role inlung immunopathology (23).

Future researchThe following unanswered questions regarding SARSpathogenesis are highly relevant to the design ofprevention and control strategies. What is the initial site ofviral replication? Is SARS primarily targeted to the lung likePRCV with faecal shedding of swallowed virus and withundefined sequelae contributing to the diarrhoea cases?Alternatively, is SARS CoV pneumoenteric like BCoV, withvariable degrees of infection of the intestinal andrespiratory tracts and is disease precipitated by the co-factors discussed or by unknown variables? Does SARSCoV infect the lung directly or via viraemia after initialreplication in another site (oral cavity, tonsils, upperrespiratory tract) and does the virus productively infectsecondary target organs (intestine, kidney) via viraemiaafter replication in the lung?

Finally, the persistent, macrophage tropic, systemic FIPVinfection of cats presents yet another CoV disease modeland a dilemma for attempted control strategies. In thisdisease scenario, induction of neutralising IgG antibodiesto the FIPV S protein, not only fails to prevent FIPVinfections, but actually potentiates theimmunopathogenesis of FIPV. This occurs via generation ofimmune complexes with activation of complement, or itmay be the result of antibody-dependent enhancement ofFIPV infection of macrophages, as has been observed invitro (63).

The suspected zoonotic origin of SARS CoV (24, 101) andthe recognised propensity of several CoVs to cross speciesbarriers, illustrate the need for additional animal studies ofthe mechanisms of interspecies transmission of CoVs andtheir adaptation to new hosts. The possible animalreservoir for SARS remains undefined. At present, verylittle is understood about CoVs or other viruses circulatingin wildlife or their potential to emerge or recombine withnew or existing CoVs (80) as public or animal healththreats.

ConclusionsIn summary, studies of animal CoV infections in thenatural host provide enteric and respiratory disease modelswhich enhance the understanding of both the similaritiesand divergences of CoV disease pathogenesis and targetsfor control. Several reviews of animal CoV vaccines in thecontext of the development of vaccines for SARS haverecently been made available or are in press (71, 72).


Certainly, SARS has highlighted the need for closer contact,communication and collaboration between veterinaryscientists and the medical community to address emergingzoonotic public health threats. Hopefully, the SARSepidemic will generate new interest, collaborations andfunding for these fundamental research questionsapplicable not only to SARS CoV, but also to the estimated75% of newly emerging human diseases arising aszoonoses (87). A summary of the lessons learned fromSARS and several strategies that should be implementedbased on these lessons follows.

Lessonsa) Coronaviruses were long-recognised and studied byveterinary scientists as major causes of potentially fatalrespiratory and enteric infections in animals. Moreover,such studies emphasised the potential of CoVs forinterspecies transmission, but the medical researchcommunity was largely unaware of these findings or theirimplications for public health based on experiences withlow impact human CoV infections. This knowledge basefrom research on animal CoVs contributed significantly tothe rapid progress in the characterisation of SARS CoV andwill enhance the future development and testing ofvaccines and antivirals for SARS.

b) Given that an estimated 75% of newly emergingpathogens in humans are zoonotic and based onexperiences with SARS CoV, veterinary scientists areessential partners for disease control and public healthmanagement. Their input and assistance should involvethe identification and management of animal reservoirs fornewly emerged zoonotic pathogens.

c) Local events in the People’s Republic of China rapidlytriggered a global epidemic within only a few weeks.International co-operation and collaboration, withestablished working relationships and access to moderncommunication tools (secure networks via the internet,teleconferences, electronic reporting systems, includingnon-governmental sources such as Pro-Med) were essentialfor the co-ordination and implementation of effortsrequired for the identification and control of SARS. Boththe established international network for influenza virussurveillance initiated by the WHO, and the USA CDCplayed major roles in these efforts.

d) Few established mechanisms exist to promoteinteragency co-operation (animal and public healthagencies, both national and international) in investigatingand controlling outbreaks mediated by newly emerging orre-emerging zoonotic pathogens.

e) Containment of the SARS epidemic relied on traditionalmethods of initial disease identification (virus isolation,electron microscopy characterisation, serology) andcontainment (quarantine and trace-backs) adapted to theenvironments of the 21st Century (airports, aeroplanes,

population centres, hospital intensive care units, etc.).Rapid global travel, ‘super-spreaders’ and infection ofhealth care workers intensified the epidemic. Countrieswhich rapidly implemented and enforced control measuresmanaged to contain the epidemic; other countries withdelayed responses experienced more devastatingconsequences. Even within the limited time-frame of theepidemic and the major foci of infections contained withina few countries, the cost of the SARS epidemic wasextraordinary, estimated at US$40 billion in total orapproximately US$5 million per infected patient.

Strategiesa) Veterinary scientists with appropriate expertise shouldbe recruited in the initial stages of suspected zoonoticdisease outbreaks to interact as partners with their medicalcounterparts at all stages of the outbreak investigation andcontrol process, with the major emphasis placed on thestudies and reagents needed to identify and control theanimal host reservoir. There are several organisationswhich could be a source of information on experts invarious fields, as follows:

– the World Organisation for Animal Health (OIE) hasdesignated experts for various animal disease entitieswhose expertise could be sought by national andinternational agencies

– federal granting agencies, federal agencies anduniversities have lists of scientists with disease expertisebased on grant and publication records who could berecruited to provide advice on a specific pathogen.

b) Closer research ties and interagency funding and co-operation are required to provide grants to academicresearchers to promote collaborative infectious andzoonotic disease research between medical and veterinaryscientists and to provide training funds for students in thisarea, as follows:

– to study disease pathogenesis in the most appropriateanimal models, including the natural host, and to elucidatenovel mechanisms of disease in animals, including diseasespresently lacking a human counterpart

– to identify the animal reservoir of zoonotic pathogensand to develop and validate diagnostic assays targeted todetect such zoonotic agents in animals to study the chainof interspecies transmission. Species-specific reagents arelacking to conduct immunological tests for antibodies tothe zoonotic pathogens in the various host species

– to enable teams of medical and veterinary scientists toassemble collections of zoonotic pathogens from human andanimal sources and conduct comparative studies to assesspathogen evolution and the changes that occur uponadaptation to new hosts. Both historical and recent animaland human microbial collections should be maintained andbe made available through reference centres such as theAmerican Type Culture Collection in Manassas, VA, USA.


c) The failure to identify the animal reservoir for SARSCoV or to develop diagnostic tests for the disease, validatedfor use in diverse animal populations, remains a concernfor the re-emergence of SARS from an animal reservoir.Consequently, there is a need to develop and validateassays and reagents and implement an integrated diseasesurveillance system encompassing wildlife, domesticanimals and humans.

d) Co-operation and co-ordination of efforts among animaland public health agencies with input from internationaldisease experts is essential to establish this system, asfollows:

– collaborative funds must be provided to study thefactors that promote interspecies transmission ofpathogens and the mechanisms involved

– contingency funds must be provided to rapidlyassemble interdisciplinary teams with the targeted diseaseand disciplinary expertise (i.e. in methods and strategiesfor detection, diagnosis, response, recovery and preventionin both the animal and human populations) to address anewly emerging disease in an integrated manner. Suchteams require the necessary infrastructures (BSL-3laboratories and animal facilities, etc.) to conduct targetedand integrated work

– rotating, short-term fellowships must be provided forveterinary scientists to undertake co-operative projects

with their medical counterparts at medical schools andpublic health laboratories, the USA CDC, WHO, etc., andfor medical scientists to rotate through the counterpartorganisations such as Colleges of Veterinary Medicine,veterinary diagnostic laboratories, the United StatesDepartment of Agriculture, the OIE, the Food andAgriculture Organization, etc. This will foster closer tiesbetween the various organisations and favour thenetworking required in emergencies to address themultifaceted aspects of emerging zoonotic diseaseoutbreaks in a more integrated manner

– international exchange and training programmes andco-operative grants must also be provided for scientistsfrom developing countries to enhance disease monitoringand control efforts and to foster mutual trust andinternational co-operation.

e) Better containment and universal and rapiddisinfection/detection procedures (airports, passengers,baggage, hospitals, etc.) are required for application to the21st Century environment. Moreover, highly effectivecontrol measures for more rapidly spreading aerosolrespiratory pathogens need to be developed.

f) Government co-operation at all levels and transparencyin reporting animal and human disease outbreaks arerequired to contain regional outbreaks and preventpandemics.


L.J. Saif

RésuméEn 2002, un nouveau coronavirus responsable d’un syndrome respiratoire aigusévère (SRAS) et mortel pour l’homme fait son apparition en Républiquepopulaire de Chine. L’épidémie se propage rapidement dans le monde avantd’être endiguée en 2003, même si quelques cas sporadiques continuent à semanifester en Asie après cette date. Le virus serait d’origine zoonotique et issud’un réservoir animal sauvage (civettes [Paguma larvata]), mais l’identité de sonhôte n’a toutefois pas été établie. L’éventualité d’une transmission ducoronavirus du SRAS aux rongeurs ou aux chats domestiques (prouvée par voieexpérimentale) et d’une perpétuation de la maladie chez ces espèces suscitel’inquiétude. Les coronavirus sont reconnus responsables de plusieursinfections entériques et respiratoires du bétail et de la volaille dont l’issues’avère souvent fatale pour les jeunes animaux. L’émergence du SRAS a surprisla communauté médicale, même si des spécialistes vétérinaires des coronavirusen avaient déjà isolé chez des animaux sauvages et fait état dans leurspublications d’une transmission interspécifique aux bovins. De surcroît, lesscientifiques détenaient les preuves incontestables de l’émergence de nouvellessouches de coronavirus et de la mutation des souches existantes, conduisant àl’apparition de nouveaux syndromes de maladie chez les animaux, mais la justemesure de l’évolution et de l’impact pathologique des coronavirus n’avait pas été

Les coronavirus animaux et leur enseignement pour le syndromerespiratoire aigu sévère


prise avant l’épidémie de SRAS. Cette étude porte notamment sur lapathogénèse comparée des infections à coronavirus et sur les facteursaggravants de l’affection respiratoire dans le contexte particulier de l’élevagebovin et de l’aviculture. Elle vise à améliorer notre connaissance de latransmission des coronavirus et des mécanismes pathologiques susceptiblesd’intervenir dans le SRAS. Par ailleurs, elle met en évidence la contribution deschercheurs vétérinaires à cet effort. Ces exemples témoignent de la nécessité,pour les communautés vétérinaires et médicales de communiquer entre elles etde collaborer à la compréhension et à la lutte contre les maladies zoonotiquesémergentes du XXIe siècle.

Mots-clésCoronavirus animal – Coronavirus entérique et respiratoire – Syndrome respiratoire aigusévère – Zoonose.

L.J. Saif

ResumenEn 2002, un nuevo coronavirus asociado al síndrome respiratorio agudo severo(SRAS) y mortalidad en el hombre, emergió en la República Popular China. Laepidemia se extendió con celeridad por el mundo antes de quedar bajo controlen 2003, aunque posteriormente siguieran registrándose casos esporádicos enAsia. Se presume que el virus es de origen zoonótico y cuenta con un reservorioentre la fauna salvaje (la civeta [Paguma larvata]), pero se ignora cuál es suhuésped definitivo. La posibilidad de que el coronavirus asociado al SRAS setransmita a roedores o gatos domésticos (fenómeno ya descrito en condicionesexperimentales) y perpetúe la enfermedad en esas especies es preocupante. Sesabe que los coronavirus provocan infecciones intestinales y respiratorias enganado y aves de corral, que a menudo resultan mortales en animales jóvenes.Aunque la aparición del SRAS sorprendió a la comunidad médica, el aislamientode coronavirus en animales salvajes y su transmisión al ganado han sidodescritos con anterioridad por coronavirólogos veterinarios. Además, loscientíficos disponían de una serie de sólidos indicios que apuntaban a laaparición de cepas, nuevas o mutantes, capaces de provocar nuevos síndromesen animales. Sin embargo, antes del SRAS no había conciencia general de loscambios que estaban experimentando los coronavirus y del peligro sanitario queello encerraba. El autor describe un estudio comparativo de la patogénesis delas infecciones por coronavirus (incluyendo los factores agravantes de laenfermedad respiratoria que provocan), centrándose especialmente en elganado y las aves de corral. Con ello pretende ofrecer elementos que aclaren latransmisión y patogenia de estos virus y que posiblemente puedan aplicarse alcaso del SRAS, subrayando al mismo tiempo la contribución de la comunidadcientífica veterinaria en este terreno. Estos ejemplos ponen de relieve el hechode que para entender y controlar las enfermedades zoonóticas emergentes delsiglo XXI es absolutamente necesario que la profesión médica y la veterinaria secomuniquen y trabajen concertadamente.

Palabras claveCoronavirus animal – Coronavirus intestinal y respiratorio – Síndrome respiratorio agudosevero – Zoonosis.

¿Qué pueden enseñarnos los coronavirus animales sobre elsíndrome respiratorio agudo severo?


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