Canine Respiratory Viruses

Vet. Res. 38 (2007) 355–373 355 c INRA, EDP Sciences, 2007 DOI: 10.1051/vetres:2006058 Review article

Canine respiratory viruses

Canio B*, Vito M

Department of Animal Health and Wellbeing, Faculty of Veterinary Medicine of Bari, Italy

(Received 27 April 2006; accepted 28 August 2006)

Abstract – Acute contagious respiratory disease (kennel cough) is commonly described in dogs worldwide. The disease appears to be multifactorial and a number of viral and bacterial pathogens have been reported as potential aetiological agents, including canine parainﬂuenza virus, canine adenovirus and Bordetella bronchiseptica, as well as mycoplasmas, Streptococcus equi subsp. zooepidemicus, canine herpesvirus and reovirus-1,-2 and -3. Enhancement of pathogenicity by multiple infections can result in more severe clinical forms. In addition, acute respiratory diseases associated with infection by inﬂuenza A virus, and group I and II coronaviruses, have been described recently in dogs. Host species shifts and tropism changes are likely responsible for the onset of these new pathogens. The importance of the viral agents in the kennel cough complex is discussed.

kennel cough / respiratory disease / dogs / viruses

Table of contents 1. Introduction ...... 355 2. Canine adenovirus type 2 ...... 356 3. Canine herpesvirus ...... 357 4. Canine inﬂuenzavirus...... 359 5. Canine parainﬂuenzavirus ...... 360 6. Canine reovirus...... 362 7. Canine respiratory coronavirus ...... 363 8. Pantropic canine coronavirus...... 364 9. Conclusions ...... 365

1. INTRODUCTION Mild to severe episodes of cough and respiratory distress are characteristic clin- Infectious tracheobronchitis (ITB) or ical features recognized in aﬀected dogs. kennel cough is the term used by veterinar- ITB has worldwide distribution and is rec- ians to describe an acute, highly contagious ognized as one of the most prevalent infec- respiratory disease in dogs aﬀecting the tious diseases of dogs. The disease is fre- larynx, trachea, bronchi, and occasionally quently described in dogs housed in groups the nasal mucosa and the lower respiratory in rehoming centers and boarding or train- tract [6]. ing kennels. * Corresponding author: Two clinical forms of ITB have been de- [email protected] scribed. The uncomplicated form is most

Article available at http://www.edpsciences.org/vetres or http://dx.doi.org/10.1051/vetres:2006058 356 C. Buonavoglia, V. Martella common and is characterized as a dry, with particular regards to newly described hacking cough, often in association with viruses, is reported. gagging and retching behavior. The dogs ff are a ected by a self-limiting, primarily 2. CANINE ADENOVIRUS TYPE 2 viral infection of the trachea and bronchi. A complicated form of ITB is described Canine adenovirus type 2 (CAV-2) de- in puppies or immuno-compromised dogs. termines unapparent to mild infection of In the complicated forms, secondary bac- the respiratory tract and is regarded as one terial infections and involvement of pul- of the causes of the common widespread monary tissue overlaps the viral process. ITB [154]. CAV-2 has also been implicated The cough is associated with mucoid dis- in episodes of enteritis [76, 98] and has charges. The condition may progress to been detected in the brain of dogs with bronchopneumonia and, in the most severe neurological signs [19]. instances, to death [6]. The virus was first detected in 1961, ff Multiple agents, bacterial and viral, are in Canada, from dogs a ected by laryngotracheitis [55]. The isolate, strain Toronto implicated in the aetiology of ITB. Co- / isolation of viral and bacterial pathogens A26 61, was characterized as an aden- is frequent, while experimental infections ovirus, and was initially considered to be with single pathogens may result in sub- an attenuated strain of canine adenovirus clinical or mild forms of disease, suggest- type 1 (CAV-1). Subsequently, structural and antigenic differences were observed ing a multi-factorial pathogenesis. Many / agents likely play a role in ITB, such and strain A26 61 was proposed as the as canine parainfluenza virus [2], canine prototype of a distinct canine adenovirus, adenovirus [55], Bordetella bronchisep- designated as type 2 (CAV-2) [65, 75, 104, 107, 152, 172]. CAV-1 and CAV-2 were tica [18], and mycoplasmas [36, 128]. ff Streptococcus equi subsp. zooepidemicus, found to be genetically di erent by restric- has been associated with severe to fa- tion endonuclease analysis [10, 75] and by tal respiratory forms in dogs alone or in DNA hybridization [106]. The complete mixed infections [36, 61, 173]. Recently, sequence analysis of both the CAV-1 and outbreaks of influenza A virus, initially CAV-2 genome has revealed about 75% misdiagnosed as ITB, have been reported nucleotide identity [49, 114]. Although in the USA [45,173]. In addition, novel ca- CAV-1 and CAV-2 are related genetically nine coronaviruses, a pantropic variant of and antigenically [109,168], they have dif- CCoV type II [29] and the canine respira- ferent tissue tropism. Vascular endothelial tory coronavirus virus, CRCoV [60], have cells and hepatic and renal parenchymal been detected from the respiratory tract cells are the main targets of CAV-1, while of either symptomatic or asymptomatic the respiratory tract epithelium and, to a dogs. Canine herpesvirus and reovirus-1,- limited degree, the intestinal epithelium, are the targets of CAV-2 [3, 140, 153]. In 2,-3 have rarely been reported from dogs ff with kennel cough but are not thought addition, the two types display di erent to play a major role in the disease com- hemagglutination patterns [105]. plex [86,97]. Vaccines are available against Infection with CAV-2 appears to be some of these infectious agents but regular widespread in dogs that are not immune to vaccination in kennels often fails to prevent CAV-1 or CAV-2. CAV-2 was isolated from ITB. 34 out of 221 throat swabs of pups with and without respiratory signs that were taken An overview of the viral agents that to a veterinarian for vaccination [4]. Like- have been associated with ITB in dogs, wise, pups in pet shops and in laboratory Canine respiratory viruses 357 animal colonies were found to carry CAV-2 lung lesions can be extensive. When addi- in the respiratory tract [6,20]. By converse, tional bacterial or viral agents are involved, CAV-2 was not detectable in dogs vacci- the ITB complex can be observed [5, 6]. nated in a rehoming center [61]. Antibodies to CAV-2 antigens have The host range of CAV-2 includes been demonstrated by hemagglutination- a broad number of mammalian species. inhibition, agar gel diffusion, virus precipi- Wild-life animals may be a source of in- tation, complement fixation and by neutral- fection for domestic dogs. The overall ization [90]. Protection appears to correlate prevalence of antibodies to canine aden- with the neutralizing antibody levels [3,8]. oviruses in European red foxes (Vulpes Nasal or throat swabs appear to be suit- vulpes) in Australia was 23.2% with able for virus isolation. Primary dog kid- marked geographical, seasonal and age dif- ney cells have been used successfully for ferences [134], while the prevalence of an- isolation and cultivation of CAV-2 [55]. tibodies was 97% in Island foxes (Urocyon However, a variety of cell lines are simi- littoralis) in the Channel Islands, Califor- larly susceptible to CAV-2 and to CAV-1 nia [70]. Antibodies to CAV-2 were also [171]. Demonstration of CAV-2 antigen by detected in free-ranging terrestrial carni- immunofluorescence in acetone-fixed lung vores and in marine mammals in Alaska sections or tissue imprints is used for di- and Canada, including black bears (Ursus agnosis of CAV-2. A polymerase chain americanus), fishers (Martes pennanti), reaction (PCR) assay has been developed polar bears (Ursus maritimus), wolves to detect canine adenoviruses and to dis- (Canis lupus), walruses (Odobenus ros- tinguish between CAV-1 and CAV-2 [82]. marus) and Steller sea lions (Eumetopias Modified live CAV-2 vaccines proved jubatus) [30,120,147]. to be highly effective in reducing the cir- The route of infection of CAV-2 is oro- culation of CAV-2 in canine populations. nasal. The virus replicates in non-ciliated Dogs vaccinated with CAV-2 develop im- bronchiolar epithelial cells, in surface cells munity to both CAV-1 and CAV-2 [3, 8]. of the nasal mucosa, pharynx, tonsillar In a similar fashion, dogs vaccinated with crypts, mucous cells in the trachea and CAV-1 develop immunity to both CAV-1 bronchi in peribronchial glands and type and CAV-2 [43]. However, the use of 2 alveolar epithelial cells. In addition to CAV-2 for immunization of pups against these tissues, the virus can be isolated both canine adenovirus types has elimi- from retropharyngeal and bronchial lymph nated safety side-effects encountered with nodes as well as from the stomach and CAV-1 vaccines, i.e. the occurrence of oc- the intestine. The peak of replication is ular lesions [24,48,90]. Maternally-derived reached by 3–6 days post infection. Sub- antibodies in pups may prevent active im- sequently, virus loads rapidly decline, in munization after vaccine administration up relation to the production of antibodies, to the age of 12-16 weeks [8]. Vaccine and CAV-2 usually can not be isolated by administration by the intranasal route has 9 days post infection. Respiratory signs been proposed to overcome the interfer- are consistent with damage of bronchial ence of maternal antibodies [8], but prod- epithelial cells. There may be evidence ucts for intranasal vaccination are not mar- of narcotising bronchitis or bronchiolitis keted. and of bronchiolitis obliterans. Infection of type 2 alveolar cells is associated with in- 3. CANINE HERPESVIRUS terstitial pneumonia [5, 6, 9, 35, 47, 90]. Dogs exposed to CAV-2 alone rarely Canine herpesvirus (CHV) is a mem- show spontaneous disease signs, although beroftheAlphaherpesvirinae subfamily 358 C. Buonavoglia, V. Martella of the Herpesviridae [159]. CHV was first pears to be mediated by heparan sulfate, described in the mid 1960s from a fatal as observed for FHV and for other her- septicemic disease of puppies [32]. Infec- pesviruses [99, 116]. tion of susceptible puppies of less than After both symptomatic and asymp- two weeks of age may result in fatal gen- tomatic infections, dogs remain latently in- eralized necrotizing and hemorrhagic dis- fected and virus may be excreted at unpre- ease, while pups older than two weeks and dictable intervals over periods of several adult dogs often do not show any clinical months, or years. Reactivation of latent signs [32]. Infection in older dogs appears virus may be provoked by stress (move- to be restricted to the upper respiratory ment to new quarters, introduction of new tract [7]. CHV is also transmitted transpla- dogs) or, experimentally, by immunosup- centally, resulting in fetal death [77]. pressive drugs (corticosteroids) or antilym- Serological surveys have shown a rela- phocyte serum. Latent virus, demonstrated tively high prevalence of CHV in house- by the polymerase chain reaction, persists hold and colony-bred dogs. The prevalence in the trigeminal ganglia, but other sites of antibodies in dogs was 88% in Eng- such as the lumbo-sacral ganglia, tonsils, land, 45.8% in Belgium, and 39.3% in and parotid salivary gland have been iden- the Netherlands [129, 133, 135]. Serologi- tified [31, 33, 112, 119]. cal studies in Italy have revealed a simi- Canine herpesvirus has been detected in lar prevalence in kennelled dogs (27.9%), dogs with ITB [22] but its role remains while the prevalence was lower in pets controversial. Experimental infection has (3.1%) [142]. been shown to cause mild clinical symp- The host range of CHV is restricted to toms of rhinitis and pharyngitis [7] or to dogs [91]. However, antibodies to CHV result in ITB-related disease [85]. Experi- have been detected in the sera of European mental infection by the intravenous route red foxes (Vulpes vulpes) in Australia [134] in adult foxes results in fever, lethargy and and Germany [156] and in sera of North respiratory signs, while peroral infection American river otters (Lontra canadensis) does not [131]. from New York State [88], while a CHV- A long-term survey in a population like virus has been isolated from captive of dogs in a rehoming center has evi- coyote pups [64]. denced CHV in 9.6% of lung and 12.8% CHV appears to be a monotypic virus, of tracheal samples. CHV infections oc- as defined by antigenic comparison of var- curred later than other viral infections. In ious isolates [32, 122]. The gene structure contrast to CRCoV and CPIV, that were de- of CHV has yet to be determined, since tected more frequently within the first and no CHV strain has been completely se- second week, respectively, CHV was de- quenced and only a few genes have been tected more frequently at weeks 3 and 4 identified [73, 96, 132]. Restriction map- after dog introduction in the kennel. Inter- ping, southern blot hybridization and se- estingly, CHV infection was apparently re- quence analysis have shown that the over- lated to more-severe respiratory signs [61]. all structure of CHV resembles those of Whether the presence of CHV is responsi- other alphaherpesviruses and that CHV is ble for increased disease severity or vice- genetically related to feline herpesvirus versa is not clear. In a 1-year study in (FHV-1), phocid herpesvirus 1 and to the training centers for working dogs, sero- equid herpesviruses 1 and 4 [103,130,138, conversion to CHV appeared to be more 169]. frequent in dogs infected by CRCoV [62], Like other herpesviruses, attachment of a finding that is more consistent with virus CHV to permissive cells (MDCK) ap- reactivation after disease-induced stress. Canine respiratory viruses 359

An inactivated, subunit vaccine has detected in the sera of dogs by hemaggluti- been available in Europe since 2003. The nation inhibition and serum neutralization vaccine is specifically indicated for bitches assays, suggesting a possible exposure of during pregnancy. The vaccine was shown dogs to human influenza viruses [28]. to provide good immunity to newborn pups The first documented evidence of in- after two injections had been administered fluenza A in dogs was obtained in 2004 in to their dams. the USA, where outbreaks of severe respiratory disease were reported in Florida 4. CANINE INFLUENZAVIRUS racing greyhounds [45]. Additional outbreaks of respiratory disease were reported Influenza is globally the most eco- in 2004 in 6 states and 2005 in 11 states nomically important respiratory disease in throughout the USA and the infection was humans, pigs, horses, and in the avian also confirmed in pet dogs. These cases species. Influenza A viruses have en- occurred in animal shelters, humane soci- veloped virions of 80 to 120 nm in di- eties, rescue groups, pet stores, boarding ameter, with about 500 spikes of 10 to kennels, and veterinary clinics [45, 173]. 14 nm in length radiating outward from the The viruses were found to agglu- lipid envelope [170]. The genome is com- tinate chicken erythrocytes and two posed of eight segments of single-stranded strains were isolated in Madin-Darby RNA that segregate independently. The canine kidney cells (MDCK) from spike proteins, HA (hemagglutinin) and lung and bronchioalveolar lavage NA (neuraminidase), elicit neutralizing an- fluid [45, 173], A/ca/Florida/43/2004 tibody response and provide the basis for a and A/ca/Iowa/13628/2005. Retrospective dual classification system by H (1 to 16) serological investigation demonstrated and N (1 to 9) subtypes [67, 170]. that the virus was present before 2004, Distribution of the various subtypes is but not before 1998, and a strain, species-restricted but interspecies trans- A/eq/Florida/242/03, was isolated from missions may occur, notably between archival tissues of a greyhound that had avians and mammalians [170]. H3N2, died from hemorrhagic bronchopneumonia H2N2 and H1N1 strains have been re- in 2003 [45]. sponsible for influenza-associated disease Molecular and antigenic analyses of and mortality in the last decades in hu- influenza viruses isolated from the var- mans, while fatal infections by the highly ious influenza outbreaks in racing grey- pathogenic H7N7 and H5N1 avian strains hounds revealed that the canine strains are have occurred sporadically [41, 66, 151]. closely related to H3N8 equine influenza In pigs, influenza A infection is caused by viruses [45, 173]. The HA and NA genes H1N1 and H3N2 subtypes [27]. Two dif- of the canine isolates are genetically close ferent subtypes of equine influenza virus, (96%–98% nucleotide identity) to the HA H7N7 and H3N8, have been associated and NA genes of recent H3N8 equine with disease in horses [149, 162, 163]. Vir- influenza viruses. Sequence and phyloge- tually all the H and N subtypes have been netic analysis of all the 8 genome segments signaled in the avian species that act as a indicated that the canine influenza viruses vast, continual reservoir for mammalians form a monophyletic group, a finding that [164,170]. is consistent with a single interspecies Until recently, dogs were regarded virus transfer, and that the virus likely got unanimously as non-susceptible hosts to adapted to the canine host by accumulation influenza virus A. In the 1980s, antibod- of point mutations rather than by exchange ies to human influenza A viruses were of genome segments via reassortment with 360 C. Buonavoglia, V. Martella other influenza virus A strains, since all the crobial. In the more severe forms, pneu- genome segments are of equine origin [45]. monia is likely caused by bacterial super- Two distinct clinical forms have been infection, and responds best to hydration described in dogs infected with influenza and broad-spectrum bactericidal antimi- virus with illness rates being nearly 100%. crobials. A milder illness is described in most dogs, No vaccine is available to protect which is characterized by initial fever and dogs against canine influenza. Vaccina- then cough for 10 to 14 days, followed tion against other pathogens causing res- by recovery. The cough is usually moist, piratory disease, however, may help pre- but in some dogs can be dry and resemble vent more common respiratory pathogens the ITB complex. A thick nasal discharge from becoming secondary infections in may be described, which is usually caused a respiratory tract already compromised by a secondary bacterial infection. A per- by influenza infection. The canine in- acute death associated with haemorrhage fluenza virus appears to be easily inacti- in the respiratory tract has been observed vated by common disinfectants (e.g., qua- in about 5% of the dogs. The severe form ternary ammonium compounds and bleach is accompanied by rapid respiration and solutions). Protocols should be established high fever (40–41 ◦C). Post-mortem ex- for thoroughly cleaning and disinfecting amination of dogs dead after the peracute cages, bowls, and other surfaces between form revealed extensive haemorrhage in use, as well as for disinfections of person- the lungs, mediastinum and pleural cav- nel before and after handling of animals. ity. The lungs exhibited extensive red to There is no rapid test for direct diag- red-black discoloration with moderate to nosis of acute canine influenza virus in- marked palpable firmness. Mild fibrinous fection. Serological assays may detect an- pleuritis was also noted. Histological ex- tibodies to canine influenza virus as early amination revealed tracheitis, bronchitis, as 7 days after onset of clinical signs. In bronchiolitis and suppurative bronchop- equipped laboratories, viral isolation on neumonia. Lung sections were character- tissue cultures and reverse transcription ized by severe hemorrhagic interstitial or (RT)-PCR or real time PCR analysis may bronchointerstitial pneumonia. Patchy in- be applied to fresh lung and tracheal tissues terstitial change with alveolar septal thick- of dogs that have died from pneumonia and ening, coagula of debris in the alveoli, and to respiratory secretion specimens from ill associated atelectasis were evident, along animals. with foci of pyogranulomatous bronchointerstitial pneumonia and dilatation of air- 5. CANINE PARAINFLUENZAVIRUS ways by degenerate cells and debris. Scat- Canine parainfluenzavirus (CPIV) was tered vasculitis and vascular thrombi were first reported in the late 1960s from labora- also observed [45, 173]. The disease has tory dogs with respiratory disease [2] and been reproduced by experimental inocula- from a sentry dog with respiratory disease tion of the virus [45]. of the upper tract [44]. Subsequent studies Therapeutic administration of broad- revealed that the virus was frequent in dogs spectrum antimicrobial drugs reduces the with respiratory disease [11, 22, 42, 110, severity but can not control the dis- 137, 158], suggesting a key role, along ease [173]. In the milder forms, a thick with Bordetella bronchiseptica, in the ae- green nasal discharge, which most likely tiology of ITB. represents a secondary bacterial infection, Parainfluenza viruses include important usually resolves quickly after treatment pathogens of the respiratory tract of mam- with a broad-spectrum bactericidal antimi- mals and birds. The term parainfluenza Canine respiratory viruses 361 was originally adopted after the influenza- of infected animals for 8-10 days after in- like symptoms observed in infected pa- fection and is usually transmitted by direct tients and after the influenza-like hemag- contact with infected aerosol [6]. The virus glutination and neuraminidase activities may spread rapidly in kennels or shelters exhibited by the virus particles. Parain- where a large number of dogs are kept to- fluenza viruses are classified in the fam- gether. The virus was detected in 19.4% ily Paramyxoviridae, subfamily Paramyx- of tracheal and 9.6% of lung samples of ovirinae. CPIV is antigenically similar to dogs in a rehoming centre where ITB was the simian virus 5 (SV5) and to porcine, endemic and persisted, in spite of regu- bovine, ovine and feline parainfluenza lar vaccination against canine adenovirus viruses [1, 127]. Sequence analysis of the type-2, distemper and parainfluenza [61]. fusion protein-encoding gene has revealed There is evidence that cats, hamsters that CPIV has 99.3% nucleotide similar- and guinea pigs may naturally be in- ity to porcine parainfluenza virus, 98.5% fected with CPIV/SV5 or a very closely to SV5 and 59.5% nt to human parain- related virus [81, 144]. In addition, a fluenza virus 2 [111]. Accordingly, CPIV CPIV/SV5-like strain, termed SER, was is regarded as a host variant of SV5, within recently isolated from the lung of a fetus the genus Rubulavirus and has been ten- of a breeding sow with porcine respira- tatively proposed as parainfluenza virus 5 tory and reproductive syndrome [79, 155]. (PI-5) [39]. Viruses genetically similar to Antibodies to CPVI have been demon- SV5 have been detected in humans in more strated in 20 of 44 wildlife species in eight occasions although the relationship to any African countries [74]. Also, antibodies to human disease remains contentious [39]. CPVI have been detected in non-captive The virus is composed of a single black bears (Ursus americanus) and fishers stranded RNA genome of negative po- (Martes pennanti) in Canada [120], sug- larity and is surrounded by a lipid en- gesting circulation of CPIV-like viruses in velope of host cell origin. The genome wildlife animals. Even more interestingly, of SV5 contains seven genes that en- CPIV/SV5-like viruses may infect humans code eight proteins: the nucleoprotein and non-human primates [39]. (NP), V/phosphoprotein (V/P), matrix CPIV infection is usually restricted to (M), fusion (F), small hydrophobic (SH), the upper respiratory tract in dogs of hemagglutinin–neuraminidase (HN), and two weeks of age or older [6]. Although large (L) genes [92]. The HN protein viremia is considered an uncommon event, is involved in cell attachment to initiate CPIV has been recovered from the lungs, virus infection and mediates hemaggluti- spleen, kidneys and liver of laboratory nation [100]. In addition, HN has neu- dogs with mixed infections [22]. After ex- raminidase activity. The F protein mediates perimental infection of dogs, CPIV repli- fusion of the viral envelope with the cell cates in cells of the nasal mucosa, phar- membrane [143]. The V protein blocks in- ynx, trachea and bronchi. Small amounts terferon (IFN) signaling and inhibits IFN of virus can be recovered from the local synthesis. Interaction of the virus with the lymph nodes, but not from other lymphatic IFN system is regarded as a critical factor tissues. In naturally infected dogs, simulta- in the outcome of the infection [23,54,121, neous infections with other viral and bac- 146]. terial agents are quite common and clinical Parainfluenza is highly contagious and signs may be more severe [2, 22, 137]. the prevalence of infection appears to be Symptoms generally occur 2–8 days af- related to the density of the dog population. ter infection. CPIV produces mild symp- CPIV is excreted from the respiratory tract toms lasting less than six days, but 362 C. Buonavoglia, V. Martella infection is usually complicated by other applied to respiratory secretions, nasopha- pathogens. In the non-complicated forms, ryngeal/laryngeal swabs and tracheal/lung clinical signs include low-grade rise in tissues [61]. Serological investigations by temperature, deep sounding dry cough, wa- hemagglutination inhibition and the virus tery nasal discharge, pharyngitis and ton- neutralization test may be useful to screen sillitis [6]. Most dogs appear healthy and animals for the presence of specific anti- active. In the complicated forms, described bodies. mostly in immunocompromised animals Attenuated vaccines have been devel- or young unvaccinated puppies, the symp- oped against CPIV. A parenteral CPIV toms may progress and include lethargy, vaccine is available in combination with fever, inappetance, and pneumonia. other antigens. These vaccines alone rarely CPIV has also been isolated from a dog provide protection against contracting the with temporary posterior paralysis [63] infection, although they help to reduce the and this isolate, termed CPI+, caused severity of the disease. Vaccination of all acute encephalitis when injected intracra- animals, notably of puppies, is indicated nially into gnotobiotic dogs [13]. From one in kennels or in pet shops. Strict hygiene such experimentally infected dog, a vari- with thorough cleaning and disinfection ant, termed CPI2, was isolated that had of cages and food and water containers, phenotypic and genotypic differences from good ventilation and adequate population CPI+.CPI2isattenuatedinferretsandit density are essential for controlling virus more readily establishes persistent infec- spread. tions in tissue culture cells. The biological changes and the ability to block IFN 6. CANINE REOVIRUS signaling have been mapped to the P/V- Mammalian orthoreoviruses (MRV) are N-terminal common domain of the V pro- non-enveloped, double-stranded (ds) RNA tein [14–17,38,148]. viruses included in the genus Orthore- In experimentally infected dogs pe- ovirus within the family Reoviridae.MRV techial hemorrhages have been described are responsible for either symptomatic or in lung lobes between 3 and 8 days asymptomatic infections in mammals and post infection [2, 26]. Histological ex- possess a broad host range [157]. amination has revealed catarrhal rhinitis The reovirus genome contains ten and tracheitis with mono- and poly- dsRNA segments, which are designed as morphonuclear cell infiltrates in the mu- large (L, three segments), medium (M, cosa and submucosa. Bronchi and bron- three segments), or small (S , four seg- chioli may contain leukocytes and cellular ments) on the basis of the electrophoretic debris. mobility [118]. Three MRV serotypes have Laboratory diagnosis may rely on viral been recognized by cross-evaluation with isolation from nasopharyngeal or laryngeal specific sera in neutralization and inhi- swabs, using primary cells or cell lines bition of haemagglutination assays [136, derived from dog kidneys. A wide range 141]. Neutralization and HA activities are of canine, feline, bovine, simian, and hu- restricted to a single reovirus gene seg- man cells are permissive for CIPV and ment, S 1 [165], that encodes for the pro- monkey kidney cells have also been used teins σ1andσ1s. The σ1 protein, a fi- successfully [6]. In the first passage, the brous trimer located on the outer capsid virus usually does not induce cytopathic of the virion [68, 69], is responsible for effects and virus antigens may be demon- viral attachment on cellular receptors [95, strated by hemadsorption or immunoflu- 167], serotype-specific neutralization [12], orescence [2, 44]. RT-PCR may also be and hemagglutination [166]. Analysis of Canine respiratory viruses 363 the S 1 gene of MRV belonging to dif- tory pathogens, aggravating the course of ferent serotypes has shown a strict cor- concomitant infections [4]. relation between sequence similarity and Diagnosis of reovirus infection is usu- viral serotype [34, 56, 117]. Conversely, ally based on virus isolation on cell the other genome segments do not display cultures, electron microscopy and poly- any correlation to viral serotype, suggest- acrilamide gel electrophoresis (PAGE). ing that MRV have evolved independently These methods proved to be poorly sen- of serotype in the various species [25, 37, sitive [115] and likely underestimate the 71,87,94]. presence of MRV in animals and humans. MRV have a wide geographic distri- RT PCR protocols have been developed for bution and can virtually infect all mam- detection of MRV and for prediction of the mals, including humans [157]. In carni- MRV serotype [51, 94, 115]. vores, MRV infections have been reported sporadically, although all three serotypes 7. CANINE RESPIRATORY have been isolated from dogs and cats [21, CORONAVIRUS 46,51,57,89,97,102,108,113,145]. As in other mammalians, the aetiologi- Members of the Coronaviridae fam- cal role of MRV in respiratory diseases of ily are enveloped viruses, 80–160 nm dogs is still unclear. MRV-1 strains have in diameter, containing a linear positive- been recovered from dogs with pneumo- stranded RNA genome. Coronaviruses nia [97] or enteritis [4], in association with are currently classified into four distinct either canine distemper virus or canine par- groups based on sequence analysis and vovirus type 2. MRV-2 and MRV-3 have genome structure and on the antigenic been isolated from dogs with disease of the relationships [101, 139, 150]. The coro- upper respiratory tract [21] and with diar- navirus structural proteins include the rhea [51, 89], respectively. Only an MRV-3 spike glycoprotein, the membrane gly- enteric strain has been characterized at the coprotein and the nucleocapsid protein. molecular level in the S1andL1segments. The hemagglutinin-esterase glycoprotein The highest nucleotide identity was found is found only on the surface of group 2 to a murine strain in the S 1 segment (93%) coronaviruses [60]. and to human and bovine strains in the Three different coronaviruses have been L1 segments (90%), revealing the lack of identified in dogs thus far [60, 125]. The species-specific patterns [51]. By PCR, re- enteric canine coronaviruses (CCoV) are ovirus RNA was detected in 50/192 rectal distinguished into two genotypes, I and II, swabs from dogs with diarrhea. Also, re- and are included in group 1 coronaviruses ovirus RNA was detected in 9/12 ocular along with feline coronaviruses (FCoV) swabs, in 10/19 nasal swabs of dogs with type I and type II, transmissible gastroen- ocular/nasal discharge, whereas it was not teritis virus of swine (TGEV), porcine detected in the oro-pharynx [57]. These respiratory coronavirus (PRCoV), porcine data suggest that reoviruses are common epidemic diarrhea virus (PEDV) and hu- in dogs, both in the enteric or in the respi- man coronavirus 229E [59]. The evolution ratory tract, although the viruses are shed of CCoV is tightly intermingled with that in low amounts. Experimental infections of FCoV I and II [125]. Canine respiratory with MRV in germ- and disease-free dogs coronavirus (CRCoV) was first detected failed to give conclusive results [4, 80]. in the United Kingdom in 2003 from tra- Accordingly, it appears that MRV do not chea and lung tissues of dogs [60]. By exert direct pathogenic activity and, more phylogenetic analysis of the polymerase, likely, act in synergism with other respira- CRCoV was found to segregate with group 364 C. Buonavoglia, V. Martella

2 coronaviruses, along with bovine coro- lung fibroblasts, MDCK, HRT-18G and naviruses (BCoV) and human coronavirus fewf-4 cells were unsuccessful [60,84] and strain OC43 (HCV-OC43) [60]. Sequence this has hampered, thus far, the evaluation analysis of the S protein-encoding gene of CRCoV patho-biological properties and revealed a high genetic similarity to the the CRCoV role in canine respiratory dis- bovine strain BCoV and to the human eases. strain OC43 (96.9 and 97.1% at the nu- The role of CRCoV in ITB is not cleotide level and 96.0 and 95.2% at clear. Sero-conversion was observed in the aa level, respectively) [60], suggest- immunologically-naïve dogs after intro- ing a recent common ancestor for the duction in a kennel where infected dogs three viruses and demonstrating the occur- were housed, revealing a highly contagious rence of repeated host-species shifts [161]. nature [60]. Dogs sero-negative to CRCoV Conversely, CRCoV was found to be ge- were statistically more prone to develop netically and antigenically different from respiratory disease than dogs with antibod- the enteric canine coronaviruses (less than ies to CRCoV, providing indirect evidence 21.2% aa in the S gene). for a pathogenic role of CRCoV [60]. It By RT-PCR, CRCoV RNA has been de- is likely that CRCoV alone may induce tected both in asymptomatic and in symp- only subclinical or mild respiratory symptomatic dogs, that suffered from mild or toms. However, coronavirus replication moderate respiratory disease [60]. Analy- can damage the respiratory epithelium sis of archival samples has identified CR- and lead to bacterial superinfections. The CoV in 2 out of 126 dogs affected by human respiratory coronavirus 229E can respiratory diseases in Canada [58]. disrupt the respiratory epithelium and Taking advantage of the close genetic cause ciliary dyskinesia [40]. Accordingly, relatedness between CCRoV and BCoV, virus-induced alterations of the respiratory ELISA assays have been set up using epithelium would trigger the replication of BCoV antigen and have been used to other pathogens, causing respiratory dis- screen canine sera, revealing the presence eases resembling the ITB complex. of specific antibodies in 30.1% of dogs at the time of entry in a rehoming kennel [60]. In a further study, antibodies were de- 8. PANTROPIC CANINE tected in 22.2% and 54.2% of dogs on the CORONAVIRUS day of entry into working kennels in Lon- don and Warwickshire, respectively [62]. Enteric CCoV usually cause mild to In larger sero-epidemiological surveys, the severe diarrhea in pups, whereas fatal prevalence of CRCoV was demonstrated infections have been associated mainly to be 54.7% in North America, 36.6% with concurrent infections by canine par- in the United Kingdom [126], 17.8% in vovirus, canine adenovirus type 1 or canine Japan [84] and 32% in Italy [53] while distemper virus [50, 123, 124]. there was no evidence for CRCoV-specific Thus far, two genotypes of enteric antibodies in cats [84]. By examining CCoV have been described, namely CCoV the relationship between the age of dogs type I and CCoV type II [125]. Molecu- and the presence of CRCoV antibodies, a lar methods able to distinguish between the steady increase in the seropositivity rates two genotypes have revealed that mixed in- was observed, with the highest prevalence fections by both genotypes occur at high among dogs of 7–8 years (68.4%) [126]. frequency in dogs [52]. Attempts to isolate CRCoV from tis- Recently, a fatal, systemic disease sue of the respiratory tract, using canine caused by a highly virulent CCoV strain Canine respiratory viruses 365 was reported, which was characterized should be suspected when unexplainable by severe gastrointestinal and respiratory episodes of severe to fatal disease occur in symptoms [29]. The disease occurred in pups. Epidemiological studies are required seven dogs housed in a pet shop in the to determine whether the pantropic CCoV Apulia region, Italy. The dogs displayed strain is a new coronavirus variant emerg- fever (39.5–40 ◦C), lethargy, inappetance, ing in the canine population or if it is a respiratory distress, vomiting, hemorrhagic wide-spread infectious agent of dogs that diarrhea, and neurological signs (ataxia, usually goes undetected. Vaccination tri- seizures) followed by death within 2 days als are necessary to determine whether the after the onset of the symptoms. A marked CCoV vaccines currently available are ef- leukopenia, with total WBC counts be- fective against the highly virulent CCoV low 50% of the baseline values, was also strain. reported. Necropsy examination revealed severe gross lesions in the tonsils, lungs, liver, spleen and kidneys. Extensive lo- 9. CONCLUSIONS bar subacute bronchopneumonia was ev- idenced both in the cranial and caudal The development of new diagnostic lobes, along with effusions in the thoracic techniques and the extensive use of molec- cavity. ular analysis are quickly providing an By genotype-specific real-time RT-PCR increasing amount of information on the assays, CCoV type II RNA was detected in epidemiology of respiratory viruses, on the the intestinal content and parenchymatous molecular basis of pathogenicity and on organs, including the lungs, and a coron- the mechanisms that drive virus evolution. avirus strain was successfully isolated on In the last decades, evidence has been col- cell cultures from lungs and other tissues. lected for the emergence of novel viruses Sequence analysis of the 3’ end of the by host species shift or by change of tissue viral genome showed a point mutation in tropism due to genome mutations. Prophy- the S protein and a truncated form of the laxis of the ITB complex relies on the use nonstructural protein 3b, due to the pres- of vaccines based on selected pathogens ence of a 38-nt deletion and to a frame shift (CAV-2, CPIV and Bordetella bonchisep- in the sequence downstream of the dele- tica) and those vaccines are not always tion that introduced an early stop codon effective in preventing ITB, suggesting that in ORF3b. Either point mutations or dele- other pathogens may also play a role in tions in the structural spike glycoprotein respiratory diseases of dogs. Whether the and in the nonstructural proteins have been detection of new respiratory pathogens re- associated to changes in tropism and vir- quires the development of novel prophy- ulence of coronaviruses [72, 78, 83, 93, laxis tools is an issue that surely deserves 160]. The porcine respiratory coronavirus more attention. At the same time, intensifi- (PRCoV), a spike (S) gene deletion mu- cation of surveillance activity is paramount tant of transmissible gastroenteritis virus to monitor the emergence and spread of (TGEV), causes mild or subclinical respi- novel pathogens, to investigate their epi- ratory infections in pigs [93]. demiology and plan adequate measures of Experimental infection of dogs with the control. virus isolate resulted in a severe systemic disease that mimicked the clinical signs observed in the outbreak. However, older REFERENCES puppies were able to recover from the [1] Ajiki M., Takamura K., Hiramatsu K., infection. The pathogenic CCoV variants Nakai M., Sasaki N., Konishi S., Isolation 366 C. Buonavoglia, V. Martella

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