Review

Genetic Diversity of Canine Distemper Virus in South America

Yanina Panzera1*, Nicolás Sarute1, Lucía Carrau1, Jaime Aldaz2, Ruben Pérez1

1Sección Genética Evolutiva, Instituto de Biología, Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay; 2Escuela de Medicina Veterinaria y Zootecnia, Facultad de Ciencias Agropecuarias, Universidad Estatal de Bolívar, Guaranda, Ecuador

Abstract | Canine Distemper virus is the etiological agent of “Distemper”, the most significant infectious disease among carnivores worldwide. Herein, we present the state of the art of CDV dynamics in South America, by means of a detailed analysis of the genetic diversity, evolution, and epidemiology of the virus in several countries. Our study allowed us to establish the presence of four genetic lineages in South America, being the continent with more lineages described to date, underscoring the high genetic diversity of the circulating strains.

Editor | Muhammad Munir, The Pirbright Institute, Compton Laboratory, UK

Received | June 13, 2014; Accepted | July 25, 2014; Published | July 29, 2014

*Correspondence | Yanina Panzera, Universidad de la República, Montevideo, Uruguay; E-mail | ypanzera@fcien.edu.uy

Citation | Panzera, Y. et al. (2014). Genetic diversity of canine distemper virus in South America. British Journal of Virology, 1(2): 48-53.

The Morbillivirus is an antigenically related genus within the Paramyxoviridae which includes important mammal pathogens, such as measles virus in humans and canine distemper virus (CDV) in several carnivore species. Paramyxoviruses have a nonsegmented single-stranded negative RNA genome of 15.7 kb. CDV encodes for the nucleoprotein (N), viral polymerase (L), and phosphoprotein (P), which are associated with the genomic RNA forming the ribonucleoprotein complex; the matrix (M) is a membrane associated protein, whilst the hemagglutinin (H) and fusion (F) proteins are the antigenic determinants anchored at the viral envelope (Lamb & Parks, 2007).

CDV is the etiologic agent of canine distemper, a severe multisystemic and globally distributed disease, which represents the most important infectious threat of domestic dogs (Canis lupus familiaris) (Appel & Summers 1999). CDV infection has been reported in all families of terrestrial carnivores and several marine carnivores (Deem et al., 2000; Mamaev et al., 1995). The ability of the virus to jump between carnivores hosts is considered as one of the causes for the success of its worldwide spread. As viral reservoirs, domestic dogs pose a significant risk to captive and free-ranging wildlife species, because of dog abundance and their ability to travel for long distances (Fiorello et al., 2006). Although live attenuated vaccines have been used since 1950 to control the disease, CDV continues to cause outbreaks in receptive domestic and wild carnivores in several geographical areas (Lednicky et al., 2004; Martella et al., 2010; Woma et al., 2009; Zhao et al., 2010; Panzera et al., 2012). Distemper outbreaks registered since the 1980s in vaccinated and unvaccinated dogs, were consequence of natural infections with field strains not related to the current vaccine strains (Harder & Osterhaus, 1997; Mochizuki et al., 1999, Pardo et al., 2005; Lan et al., 2006; Calderón et al., 2007; Sarute et al., 2011). While cross-neutralization and kinetic-neutralization assays can be used to distinguish between vaccine and field strains (Appel et al., 1994; Harder et al., 1993, 1996), only molecular analyses have revealed differences between field strains.

Sequence analyses of different genes have been performed to characterize the circulating strains (Harder et al., 1996; Lednicky et al., 2004; Pardo et al., 2005; Headley et al. 2009). The H gene is the most widely employed because it has the highest variability within the CDV genome. Its analysis has led to identify geographic lineages providing important advances to the knowledge of CDV evolution worldwide (Bolt et al., 1997; Martella et al., 2006).

In South America, distemper outbreaks had apparently been known since the XVIII century in Peru, and afterwards the virus spread to Europe according to clinical and historical records (Howell, 1965; Blancou, 2004).

Figure 1. Political map of South America. In boxes are detailed the carnivores species infected with canine Distemper virus and the lineages described for each country.

The first serological reports performed in Brazil detected anti-CDV antibodies in 9% of the Amazon dog populations with no evidence for infections in wild populations (Fig. 1) (Courtenay et al., 2001). In other Brazilian regions seroprevalence surveys in domestic and wild hosts detected high antibodies titers (Fig. 1) (Headley et al., 2012).

In Bolivia, more than the 95% of the dogs had CDV antibodies, which were also detected in wild carnivores (Fig. 1) (Fiorello et al., 2006, 2007; Bronson et al. 2008).

Furthermore, in Galapagos Island, where vaccination and dog importation is forbidden, anti-CDV antibodies were detected in resident dogs (Fig. 1) (Levy et al., 2008).

In Chile, a Distemper outbreak involving two fox species occurred in 2003 (Moreira & Stutzin, 2005; Gonzalez-Acuña et al., 2003; Acosta-Jamett, 2009) and urban dogs were blamed for CDV transmission due to their high seroprevalence (Fig. 1) (Acosta-Jamett et al., 2011).

Phylogenetic analyses based on CDV strains from South America have been performed to establish the evolutionary patterns of the virus in the region. The first reports from Brazil, Argentina and Uruguay revealed that field strains clearly differed with respect to the vaccine strains (Saito et al., 2006; Calderón et al., 2007; Sarute et al., 2011).

A phylogenetic study based on a partial region of the N gene reported that Brazilian strains isolated from wild and domestic hosts were closely related and suggested that domestic dogs were the source of infection for wild carnivores (Fig. 1) (Megid et al., 2009; 2010). In 2007, Calderón analyzed a partial region of the H gene determining the presence of two genetic variants circulating in Argentina: one variant was related to European strains, while the other was unique and predominant in the country (Calderón et al., 2007). Studies based on strains isolated from free-ranging wild carnivores showed a high percentage of identity with the predominant CDV variant that affect dogs in Argentina (Fig. 1) (Ferreyra, et al. 2009).

Until 2012, the global analysis of the complete H gene had permitted the identification of eight lineages according mainly to their geographic origin: three in Europe, two in Asia, two in North America, and one in South Africa (Martella et al., 2006; An et al., 2008; Woma et al., 2009). The analysis of the full-length H gene sequences of field strains from Uruguay and Argentina, and their comparison with strains from Brazil and with strains belonging to the eight lineages, allowed us to identify two co-circulating lineages in South America which different distribution, prevalence and origin. The Uruguayan, Brazilian and one Argentinean strains clustered within a European lineage were renamed as Europe1/South America1 (EU1/SA1). The remaining Argentinean strains formed a new genetic lineage, denoted as South America 2 (SA2), that is exclusively distributed in Argentina according to the previous report of Calderón et al., (2007) (Panzera et al. 2012).

Recent studies have confirmed that all the Brazilian strains characterized from domestic dogs belong to the EU1/SA1 lineage. The absence of the other lineages in Brazil is remarkable considering the broad area of the country (47% of South America) (Negrao et al., 2013; Budaszewski et al., 2014). The predominant EU1/SA1 lineage has been circulating for at least more than a decade in southern South America. Although this lineage was previously described in Europe (Bolt et al., 1997), it is not possible to establish the genetic flow direction between both continents. Nevertheless, the high genetic homology between the South American and the European strains is indicative of a common ancestor.

Figure 2. Maximum likelihood tree constructed using the Tamura 3-parameter (I) substitution model inferred through 500 replicates for 44 South American partial sequences (630 bp) of the H gene. GenBank accession number, country, isolates and collection year are detailed. Arg: Argentina, Bra/BR: Brazil, Co: Colombia, Ec: Ecuador, Uy: Uruguay. EU1/SA1: Europe 1/South America 1, SA2: South America 2, SA3: South America 3, SA4: South America 4. A Phocid Distemper virus strain (PDV/USA2006) was used as outgroup.

Even though the lineages are defined by the complete H gene variability, its amplification directly from field samples can be difficult because of its size (1824 bp) and its transcription level which is proportionately lower in comparison to the genes located in the 3´ terminal region of the genome. These restrictions could limit its usefulness for characterization purposes. Notably, a strong phylogenetic signal was detected for the fusion protein signal-peptide (Fsp)-coding region by likelihood mapping which was as high as for the H gene. The Fsp coding region consists of only 405 bp and can be easily obtained to achieve a rapid characterization of circulating strains (Sarute et al., 2013).

A novel CDV lineage has been described based on the analysis of the Fsp region of South American strains, represented only by Ecuadorian strains and named South America (SA3), revealing the high diversity of the virus in this continent (Sarute et al., 2014).

Shortly after, phylogenetic evidence revealed a different lineage circulating among Colombian dog populations, clearly separated from the previous lineages described worldwide. Although the characterization of the Colombian lineage was performed using complete H gene sequences, and is therefore not comparable with the Fsp-coding region sequences available for the SA3 lineage; it is possible a genetic similarity between both lineages because they have similar geographic distribution in northern South America (Espinal et al., 2014). To evaluate this hypothesis, here we compared all South American strains characterized to date using a partial region of the H gene (630 bp). We built a dataset including two Ecuadorian sequences (SA3 lineage) recently published and 42 sequences of South American strains, which were employed to infer a phylogenetic tree (Fig. 2). Our finding revealed that there are currently four lineages circulating in South America: EU1/SA1, SA2, SA3 and those formed by Colombian strains, showing a high nucleotide and amino acid divergence. Therefore, the Colombian clade should be more properly denoted as South America 4 (SA4) lineage. The South American lineages have different geographical distribution, and appear spatially structured without apparent events of migration within the continent; underscoring the importance that local diversification has had in CDV dynamics.

In summary, there are currently eleven lineages circulating worldwide: three in Europe, two in Asia, two in North America, one in South Africa, and four in South America. The presence in South America of tree unique lineages and a four intercontinental one (EU1/SA1) suggest that this continent harbor the highest genetic diversity of CDV strains. The extend of variation may be even greater as only five out of the twelve South American countries have performed CDV characterization studies. This epidemiological scenario encourages additional analyses in domestic and wild species to map the geographical spread and variability of CDV variants in South America and to provide new insights into local viral diversity and evolution.

References

- • Acosta-Jamett, G. 2009: Role of domestic dogs in diseases of significance to humans and wildlife health in central Chile. PhD thesis, The University of Edinburgh, London, United Kingdom.
- • Acosta-Jamett, G., W.S.K. Chalmers, A.A. Cunningham, S. Cleaveland S, I.G. Handel and B.M. de C. Bronsvoort, 2011: Urban domestic dog populations as a source of canine distemper virus for wild carnivores in the Coquimbo region of Chile. Veterinary Microbiology, 152, 247-257.
- • An, D.J., S.H. Yoon, J.Y. Park, I.S. No and B. Park, 2008: Phylogenetic characterization of Canine Distemper Virus isolates from naturally infected dogs and a marten in Korea. Veterinary Microbiology, 132, 389–395.
- • Appel, M.J.G., R.A. Yates, G.L. Foley, J.J. Bernstein, S. Santinelli, L.H. Spelman, L.D. Miller, L.H. Arp, M. Anderson, M. Barr, S. Pearce-Kelling and B.A. Summers, 1994: Canine distemper epizootic in lions, tigers, and leopards in North America, Journal of Veterinary Diagnostic Investigation, 6, 277-288.
- • Appel, M.J. G. and B.A Summers, 1999: Canine Distemper: Current Status, Recent Advances in Canine Infectious Diseases, Carmichael, L.E. Ed. International Veterinary Information Service.
- • Budaszewski, R.F., L.D. Pinto, M.N. Weber, E.T. Caldart, C.D. Alves, V. Martella, N. Ikuta, V.R. Lunge and C.W. Canal, 2014: Genotyping of canine distemper virus strains circulating in Brazil from 2008 to 2012, Virus Research, 180, 76-83.
- • Blancou, J., 2004: Dog distemper: imported into Europe from South America?, Historia Medicina Veterinaria, 29, 35-41.
- • Bolt, G., T.D. Jensen, E. Gottschalck, P. Arctander, and M.J.G Appel, 1997: Genetic diversity of the attachment (H) protein gene of current field isolates of canine distemper virus, Journal of General Virology, 78, 367–372.
- • Bronson, E., L.H. Emmons, S. Murray, E.J. Dubovi and S.L. Deem, 2008: Serosurvey of pathogens in domestic dogs on the border of Noël Kempff Mercado National Park, Bolivia, Journal of Zoo and Wildlife Medicine, 39, 28-36.
- • Calderón, M.G., P. Remorini, O. Periolo, M. Iglesias, N. Mattion and J. La Torre, 2007: Detection by RT-PCR and genetic characterization of canine distemper virus from vaccinated and non-vaccinated dogs in Argentina, Veterinary Microbiology, 125, 341–349.
- • Courtenay, O., R.J. Quinnell and W.S. Chalmers, 2001: Contact rates between wild and domestic canids: no evidence of parvovirus or canine distemper virus in crab-eating foxes, Veterinary Microbiology, 81, 9-19.
- • Deem, S.L., L.H. Spelman, R.A. Yates and R.J. Montali, 2000: Canine distemper in terrestrial carnivores: a review. Journal of Zoo and Wildlife Medicine, 31, 441-451.
- • Espinal, M.A., F.J. Díaz and J. Ruiz-Saenz, 2014: Phylogenetic evidence of a new canine distemper virus lineage among domestic dogs in Colombia, South America, Veterinary Microbiology, 172, 168-176.
- • Ferreyra, H., M.G. Calderón, D. Marticorena, C. Marull and L. Barrios Caro, 2009: Canine distemper infection in crab-eating fox (Cerdocyon thous) from Argentina, Journal of Wildlife Diseases, 45, 1158–1162.
- • Fiorello, C.V., A.J. Noss, and S.L. Deem, 2006: Demography, hunting ecology and pathogen exposure of domestic dogs in the Isoso of Bolivia, Conservation Biology, 20, 762-771.
- • Fiorello, C.V., A.J. Noss, S.L. Deem, L. Maffei and E.J. Dubovi, 2007: Serosurvey of small carnivores in the Bolivian Chaco, Journal of Wildlife Disease, 43, 551-557.
- • González-Acuña, D., R. Ortega-Vasquez, P. Rivera-Ramírez, J. Cabello-Cabalin, 2003: Verdacht auf Staupe beim Graufuchs (Pseudalopex griseus) im mittleren Chile (Fallbericht), Zeitschrift für Jagdwissenschaft, 49, 323-326.
- • Harder, T.C., K. Klusmeyer, H.R. Frey, C. Orvell and B. Liess, 1993: Intertypic differentiation and detection of intratypic variants among canine and phocid morbillivirus isolates by kinetic neutralization using a novel immunoplaque assay, Journal of Virological Methods, 41, 77-92.
- • Harder, T.C., M. Kenter M, H. Vos, K. Siebelink, W. Huisman, G. van Amerongen, C. Orvell, T. Barrett, M.J.G. Appel and A.D. Osterhaus, 1996: Canine distemper virus from diseased large felids: biological properties and phylogenetic relationships, Journal of General Virology, 77, 397-405.
- • Harder, T.C. and A.D. Osterhaus, 1997: Canine distemper virus-a morbillivirus in search of new hosts?, Trends in Microbiology, 5, 120-124.
- • Headley, S.A., A.M. Amude, A.F. Alfieri, A.P. Bracarense, A.A. Alfieri and B.A. Summers, 2009: Molecular detection of Canine distemper virus and the immunohistochemical characterization of the neurologic lesions in naturally occurring old dog encephalitis, Journal of Veterinary Diagnostic Investigation, 21, 588-597.
- • Headley, S.A., A. M. Amude, A. F. Alfieri, A. P. Bracarense and A. A. Alfieri, 2012: Epidemiological features and the neuropathological manifestations of canine distemper virus-induced infections in Brazil: a review, Semina: Ciências Agrárias, 33, 1945-1978.
- • Howell, D.G., 1965: Bacterial and viral disease, British Veterinary Journal, 121, 398-401.
- • Lamb, R.A. and G.D. Parks, 2007: Paramyxoviridae: the viruses and their replication. In: Fields B.N., Knipe D.V., Howley, P.M., editors. Fields Virology. Lippincott Williams & Wilkins, 5th Ed. 1449–1496.
- • Lan, N.T., R. Yamaguchi, A. Inomata, Y. Furuya, K. Uchida, S. Sugano and S. Tateyama, 2006: Comparative analyses of canine distemper viral isolates from clinical cases of canine distemper in vaccinated dogs, Veterinary Microbiology, 115, 32–42
- • Lednicky, J.A., J. Dubach, M.J. Kinsel, T.P. Meehan, M. Bocchetta, L.L. Hungerford, N.A. Sarich, K.E. Witecki, M.D. Braid, C. Pedrak and C.M. Houde, 2004: Genetically distant American Canine distemper virus lineages have recently caused epizootics with somewhat different characteristics in raccoons living around a large suburban zoo in the USA, Virology Journal, 2, 1:2.
- • Levy, J.K., P.C. Crawford, M.R. Lappin, E.J. Dubovi, M.G. Levy, R. Alleman, S.J. Tucker and E.L. Clifford, 2008: Infectious diseases of dogs and cats on Isabela Island, Galapagos. Journal of Veterinary Internal Medicine, 22, 60-65.
- • Mamaev, L. V., N.N. Denikina, S.I Belikov, V.E.Volchkov, I.K. Visser, M. Fleming, C. Kai, T.C. Harder, B. Liess, and D. Osterhaus,1995; Characterisation of morbilliviruses isolated from Lake Baikal seals (Phoca sibirica).Veterinary microbiology, 44, 251-259.
- • Martella, V., G. Elia, M. Lucente, N. Decaro and E. Lorusso, A.L. Bellacicco, M. Blixenkrone-Møller, L.E. Carmichael and C. Buonavoglia, 2006: Heterogeneity within the hemagglutinin genes of canine distemper virus (CDV) strains detected in Italy, Veterinary Microbiology, 116, 301–309.
- • Martella, V., A. Bianchi, I. Bertoletti, L. Pedrotti, A. Gugiatti, A. Catella, P. Cordioli, M.S. Lucente, G. Elia and C. Buonavoglia, 2010: Canine distemper epizootic among red foxes, Italy, 2009. Emerging Infectious Diseases, 16, 2007-2009.
- • Megid, J., V.A. de Souza, C.R. Teixeira, A. Cortez, R.L Amorin, M.B. Heinemman, D.Q. and L.J. Richtzenhain, 2009: Canine distemper virus in a crab-eating fox (Cerdocyon thous) in Brazil: case report and phylogenetic analyses, Journal of Wildlife Diseases, 45, 527-530.
- • Megid, J., C.R. Teixeira, R.L. Amorin, A. Cortez, M.B. Heinemann, J.M. de Paula Antunes, L.F. da Costa, F. Fornazari, J.R. Cipriano, A. Cremasco and L.J. Richtzenhain, 2010: First identification of canine distemper virus in hoary fox (Lycalopex vetulus): pathologic aspects and virus phylogeny, Journal of Wildlife Diseases, 46, 303-305.
- • Mochizuki, M., M. Hashimoto, S. Hagiwara, Y. Yoshida and S. Ishiguro, 1999: Genotypes of canine distemper virus determined by analysis of the hemagglutinin genes of recent isolates from dogs in Japan, Journal of Clinical Microbiology, 37, 2936-2942.
- • Moreira, R. and M. Stutzin, 2005: Estudio de la Mortalidad de Zorros en la IV Región, Boletin Veterinario Oficial, 3, 1-8.
- • Negrão, F.J., N.R. Gardinali, S.A. Headley, A.A. Alfieri, M.A. Fernandez and A.F. Alfieri, 2013: Phylogenetic analyses of the hemagglutinin gene of wild-type strains of canine distemper virus in southern Brazil, Genetics and Molecular Research, 12, 2549-2555.
- • Panzera, Y., M.G. Calderón, N. Sarute, S. Guasco, A. Cardeillac, B. Bonilla, M. Hernández, L. Francia, G. Bedó, J. La Torre and R. Pérez, 2012: Evidence of two co-circulating genetic lineages of canine distemper virus in South America, Virus Research, 163, 401–404.
- • Pardo, I.D., G.C. Johnson and S.B. Kleiboeker, 2005: Phylogenetic characterization of canine distemper viruses detected in naturally infected dogs in North America, Journal of Clinical Microbiology, 43, 5009-5017.
- • Saito, T.B., A.A. Alfieri, S.R. Wosiacki, F.J. Negrão, H.S. Morais and A.F. Alfieri, 2006: Detection of canine distemper virus by reverse transcriptase-polymerase chain reaction in the urine of dogs with clinical signs of distemper encephalitis, Research in Veterinary Science, 80, 116-119.
- • Sarute, N., R. Perez, L. Francia, M. Hernández, G. Bedo and Y. Panzera, 2011: Primer diagnóstico molecular y caracterización parcial del gen de la nucleoproteína del Virus Distemper Canino en Uruguay, Veterinaria, 47, 7–13.
- • Sarute, N., M.G. Calderón, R. Perez, J. La Torre, M. Hernandez M, L. Francia and Y. Panzera, 2013: The Fusion Protein Signal-Peptide-Coding Region of Canine Distemper Virus: A Useful Tool for Phylogenetic Reconstruction and Lineage Identification, PLoS ONE 8(5): e63595. doi:10.1371/journal.pone.0063595.
- • Sarute, N., R. Pérez, J. Aldaz, A.A. Alfieri, A.F. Alfieri, D. Name, J. Llanes, M. Hernández, L. Francia and Y. Panzera, 2014: Molecular typing of canine distemper virus strains reveals the presence of a new genetic variant in South America, Virus Genes, 48, 474-478.
- • Woma, T.Y., M. van Vuuren, A.M. Bosman, M. Quan and M. Oosthuizen, 2009: Phylogenetic analysis of the haemagglutinin gene of current wild-type canine distemper viruses from South Africa: lineage Africa, Veterinary Microbiology, 143, 126–132.
- • Zhao, J.J., X.J. Yan, X.L. Chai, V. Martella, G.L. Luo, H.L. Zhang and S.P. Cheng, 2010: Phylogenetic analysis of the haemagglutinin gene of canine distemper virus strains detected from breeding foxes, raccoon dogs and minks in China, Veterinary Microbiology, 140, 32-42.