Canine distemper is a highly contagious viral disease caused by the canine distemper virus (CDV), which is a member of the Morbillivirus genus, Paramyxoviridae family. Animals that most commonly suffer from this disease belong to the Canidae family; however, the spectrum of natural hosts for CDV also includes several other families of the order Carnivora. The infectious disease presents worldwide distribution and maintains a high incidence and high levels of lethality, despite the availability of effective vaccines, and no specific treatment. CDV infection in dogs is characterized by the presentation of systemic and/or neurological courses, and viral persistence in some organs, including the central nervous system (CNS) and lymphoid tissues. An elucidation of the pathogenic mechanisms involved in canine distemper disease will lead to a better understanding of the injuries and clinical manifestations caused by CDV. Ultimately, further insight about this disease will enable the improvement of diagnostic methods as well as therapeutic studies. 1. Introduction Canine distemper is an infectious disease caused by a member of the Morbillivirus genus, Paramyxoviridae family, infecting a broad range of terrestric and aquatic carnivores. Canine distemper virus (CDV) is an enveloped virion which contains a nonsegmented single-stranded negative-sense RNA genome that encodes six structural (nucleocapsid N, matrix M, fusion F, hemagglutinin H, phospho-P and large-L proteins) and two nonstructural (C and V proteins) proteins . CDV has been reported in dogs, ferrets, wild dogs, foxes, jackals, coyotes, hyenas , lions, tigers, leopards, cheetahs , seals, sea lions, and dolphins . The domestic dog is the most suffered species, and, although the disease has been also found in big cats, CDV has not been detected in domestic cats. However, experimental infection with SPF cats revealed that this species can sustain CDV replication with pronounced lymphopenia, without displaying any clinical signs [5, 6]. The Morbillivirus genus includes other important highly infectious pathogens like measles (MV) and rinderpest viruses (RPV), and almost all members present equivalent tropism and tissue distribution in their respective hosts. Morbilliviruses are transmitted by aerosols and produce clinical similarities, such as fever, serous nasal discharge, and cough, as well as respiratory and gastrointestinal signs often complicated by secondary bacterial infections. Furthermore, the most notorious property of morbillivirus infection is the establishing of severe transitory
M. W. G. van de Bildt, T. Kuiken, A. M. Visee, S. Lema, T. R. Fitzjohn, and A. D. M. E. Osterhaus, “Distemper outbreak and its effect on African wild dog conservation,” Emerging Infectious Diseases, vol. 8, no. 2, pp. 211–213, 2002.
M. J. Appel, R. A. Yates, G. L. Foley et al., “Canine distemper epizootic in lions, tigers, and leopards in North America,” Journal of Veterinary Diagnostic Investigation, vol. 6, no. 3, pp. 277–288, 1994.
T. C. Harder, M. Kenter, H. Vos et al., “Canine distemper virus from diseased large felids: biological properties and phylogenetic relationships,” Journal of General Virology, vol. 77, no. 3, pp. 397–405, 1996.
P. B. Rossiter, “Rinderpest,” in Infectious Diseases of LivesTock with Special Reference to South Africa, J. A. W. Coetzer, G. R. Thompson, R. C. Tustin, and N. P. Kriek, Eds., vol. 2, pp. 735–757, Oxford University Press, Cape Town, South Africa, 1994.
M. J. G. Appel, W. R. Shek, and B. A. Summers, “Lymphocyte-mediated immune cytotoxicity in dogs infected with virulent canine distemper virus,” Infection and Immunity, vol. 37, no. 2, pp. 592–600, 1982.
B. Hanratty, T. Holt, E. Duffell et al., “UK measles outbreak in non-immune anthroposophic communities: the implications for the elimination of measles from Europe,” Epidemiology and Infection, vol. 125, no. 2, pp. 377–383, 2000.
P. Dhar, B. P. Sreenivasa, T. Barrett, M. Corteyn, R. P. Singh, and S. K. Bandyopadhyay, “Recent epidemiology of peste des petits ruminants virus (PPRV),” Veterinary Microbiology, vol. 88, no. 2, pp. 153–159, 2002.
V. von Messling, D. Milosevic, and R. Cattaneo, “Tropism illuminated: lymphocyte-based pathways blazed by lethal morbillivirus through the host immune system,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 39, pp. 14216–14221, 2004.
A. Beineke, C. Puff, F. Seehusen, and W. Baumg？rtner, “Pathogenesis and immunopathology of systemic and nervous canine distemper,” Veterinary Immunology and Immunopathology, vol. 127, no. 1-2, pp. 1–18, 2009.
M. C. Pardo, J. E. Bauman, and M. Mackowiak, “Protection of dogs against canine distemper by vaccination with a canarypox virus recombinant expressing canine distemper virus fusion and hemagglutinin glycoproteins,” American Journal of Veterinary Research, vol. 58, no. 8, pp. 833–836, 1997.
S. Krakowka, R. J. Higgins, and A. Koestner, “Canine distemper virus: review of structural and functional modulations in lymphoid tissues,” American Journal of Veterinary Research, vol. 41, no. 2, pp. 284–292, 1980.
R. L. de Swart, M. Ludlow, L. de Witte et al., “Predominant infection of CD150+ lymphocytes and dendritic cells during measles virus infection of macaques,” PLoS Pathogens, vol. 3, no. 11, pp. 1771–1781, 2007.
P. A. Rudd, R. Cattaneo, and V. von Messling, “Canine distemper virus uses both the anterograde and the hematogenous pathway for neuroinvasion,” Journal of Virology, vol. 80, no. 19, pp. 9361–9370, 2006.
P. L. Schwartzberg, K. L. Mueller, H. Qi, and J. L. Cannons, “SLAM receptors and SAP influence lymphocyte interactions, development and function,” Nature Reviews Immunology, vol. 9, no. 1, pp. 39–46, 2009.
V. von Messling, G. Zimmer, G. Herrler, L. Haas, and R. Cattaneo, “The hemagglutinin of canine distemper virus determines tropism and cytopathogenicity,” Journal of Virology, vol. 75, no. 14, pp. 6418–6427, 2001.
F. Seki, N. Ono, R. Yamaguchi, and Y. Yanagi, “Efficient isolation of wild strains of canine distemper virus in Vero cells expressing canine SLAM (CD150) and their adaptability to marmoset B95a cells,” Journal of Virology, vol. 77, no. 18, pp. 9943–9950, 2003.
N. Reymond, S. Fabre, E. Lecocq, J. Adela？de, P. Dubreuil, and M. Lopez, “Nectin4/PRR4, a new afadin-associated member of the nectin family that trans-interacts with nectin1/PRR1 through V domain interaction,” The Journal of Biological Chemistry, vol. 276, no. 46, pp. 43205–43215, 2001.
R. J. Geraghty, C. Krummenacher, G. H. Cohen, R. J. Eisenberg, and P. G. Spear, “Entry of alphaherpesviruses mediated by poliovirus receptor-related protein 1 and poliovirus receptor,” Science, vol. 280, no. 5369, pp. 1618–1620, 1998.
H. Ogita, Y. Rikitake, J. Miyoshi, and Y. Takai, “Cell adhesion molecules nectins and associating proteins: implications for physiology and pathology,” Proceedings of the Japan Academy Series B, vol. 86, no. 6, pp. 621–629, 2010.
A. F. Koutinas, W. Baumg？rtner, D. Tontis, Z. Polizopoulou, M. N. Saridomichelakis, and S. Lekkas, “Histopathology and immunohistochemistry of canine distemper virus-induced footpad hyperkeratosis (hard pad disease) in dogs with natural canine distemper,” Veterinary Pathology, vol. 41, no. 1, pp. 2–9, 2004.
W. Baumg？rtner, C. ？rvell, and M. Reinacher, “Naturally occurring canine distemper virus encephalitis: distribution and expression of viral polypeptides in nervous tissues,” Acta Neuropathologica, vol. 78, no. 5, pp. 504–512, 1989.
D. Laine, J. M. Bourhis, S. Longhi et al., “Measles virus nucleoprotein induces cell-proliferation arrest and apoptosis through NTAIL-NR and NCORE-FcγRIIB1 interactions, respectively,” Journal of General Virology, vol. 86, no. 6, pp. 1771–1784, 2005.
V. von Messling, N. Svitek, and R. Cattaneo, “Receptor (SLAM [CD150]) recognition and the V protein sustain swift lymphocyte-based invasion of mucosal tissue and lymphatic organs by a morbillivirus,” Journal of Virology, vol. 80, no. 12, pp. 6084–6092, 2006.
J. C. Marie, F. Saltel, J. M. Escola, P. Jurdic, T. F. Wild, and B. Horvat, “Cell surface delivery of the measles virus nucleoprotein: a viral strategy to induce immunosuppression,” Journal of Virology, vol. 78, no. 21, pp. 11952–11961, 2004.
K. Iwatsuki, M. Okita, F. Ochikubo et al., “Immunohistochemical analysis of the lymphoid organs of dogs naturally infected with canine distemper virus,” Journal of Comparative Pathology, vol. 113, no. 2, pp. 185–190, 1995.
A. Wünschmann, E. Kremmer, and W. Baumg？rtner, “Phenotypical characterization of T and B cell areas in lymphoid tissues of dogs with spontaneous distemper,” Veterinary Immunology and Immunopathology, vol. 73, no. 1, pp. 83–98, 2000.
A. Tipold, M. Vandevelde, R. Wittek, P. Moore, A. Summerfield, and A. Zurbriggen, “Partial protection and intrathecal invasion of CD8+ T cells in acute canine distemper virus infection,” Veterinary Microbiology, vol. 83, no. 3, pp. 189–203, 2001.
M. Schobesberger, A. Summerfield, M. G. Doherr, A. Zurbriggen, and C. Griot, “Canine distemper virus-induced depletion of uninfected lymphocytes is associated with apoptosis,” Veterinary Immunology and Immunopathology, vol. 104, no. 1-2, pp. 33–44, 2005.
L. Moro, A. S. Martins, C. M. Alves, F. G. A. Santos, H. L. Del Puerto, and A. C. Vasconcelos, “Apoptosis in the cerebellum of dogs with distemper,” Journal of Veterinary Medicine, Series B, vol. 50, no. 5, pp. 221–225, 2003.
S. Goodbourn, L. Didcock, and R. E. Randall, “Interferons: cell signalling, immune modulation, antiviral responses and virus countermeasures,” Journal of General Virology, vol. 81, no. 10, pp. 2341–2364, 2000.
A. R？thlisberger, D. Wiener, M. Schweizer, E. Peterhans, A. Zurbriggen, and P. Plattet, “Two domains of the V protein of virulent canine distemper virus selectively inhibit STAT1 and STAT2 nuclear import,” Journal of Virology, vol. 84, no. 13, pp. 6328–6343, 2010.
C. Griot, M. Vandevelde, M. Schobesberger, and A. Zurbriggen, “Canine distemper, a re-emerging morbillivirus with complex neuropathogenic mechanisms,” Animal Health Research Reviews, vol. 4, no. 1, pp. 1–10, 2003.
F. Seehusen, E. A. Orlando, K. Wewetzer, and W. Baumg？rtner, “Vimentin-positive astrocytes in canine distemper: a target for canine distemper virus especially in chronic demyelinating lesions?” Acta Neuropathologica, vol. 114, no. 6, pp. 597–608, 2007.
B. K. Rima, N. Duffy, W. J. Mitchell, B. A. Summers, and M. J. G. Appel, “Correlation between humoral immune responses and presence of virus in the CNS in dogs experimentally infected with canine distemper virus,” Archives of Virology, vol. 121, no. 1–4, pp. 1–8, 1991.
S. Krakowka, R. Olsen, A. Confer, A. Koestner, and B. McCullough, “Serologic response to canine distemper viral antigens in gnotobiotic dogs infected with canine distemper virus,” Journal of Infectious Diseases, vol. 132, no. 4, pp. 384–392, 1975.
W. S. Lima, R. D. Kouyos, R. J. Adams, B. T. Grenfell, and D. E. Griffin, “Prolonged persistence of measles virus RNA is characteristic of primary infection dynamics,” Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 37, pp. 14989–14994, 2012.
C. K. Ho and L. A. Babiuk, “Immune mechanisms against canine distemper. III. Role of complement lysis in the immunity and persistent infection of canine distemper virus,” Immunology, vol. 39, no. 2, pp. 231–237, 1980.
A. Wünschmann, S. Alldinger, E. Kremmer, and W. Baumg？rtner, “Identification of CD4+ and CD8+ T cell subsets and B cells in the brain of dogs with spontaneous acute, subacute-, and chronic-demyelinating distemper encephalitis,” Veterinary Immunology and Immunopathology, vol. 67, no. 2, pp. 101–116, 1999.
C. K. Ho and L. A. Babiuk, “Immune mechanisms against canine distemper. II. Role of antibody in antigen modulation and prevention of intercellular and extracellular spread of canine distemper virus,” Immunology, vol. 38, no. 4, pp. 765–772, 1979.
J. D. Gerber and A. E. Marron, “Cell-mediated immunity and age at vaccination associated with measles inoculation and protection of dogs against canine distemper,” American Journal of Veterinary Research, vol. 37, no. 2, pp. 133–138, 1976.
A. Zurbriggen, H. U. Graber, A. Wagner, and M. Vandevelde, “Canine distemper virus persistence in the nervous system is associated with noncytolytic selective virus spread,” Journal of Virology, vol. 69, no. 3, pp. 1678–1686, 1995.
A. Zurbriggen, H. U. Graber, and M. Vandevelde, “Selective spread and reduced virus release leads to canine distemper virus persistence in the nervous system,” Veterinary Microbiology, vol. 44, no. 2–4, pp. 281–288, 1995.
A. Tipold, A. Jaggy, A. Zurbriggen, and M. Vandevelde, “Neurological signs in canine distemper encephalomyelitis—a clinical study,” The European Journal of Companion Animal Practice, vol. 6, pp. 33–38, 1996.
R. J. Higgins, S. G. Krakowka, A. E. Metzler, and A. Koestner, “Primary demyelination in experimental canine distemper virus induced encephalomyelitis in gnotobiotic dogs. Sequential immunological and morphological findings,” Acta Neuropathologica, vol. 58, no. 1, pp. 1–8, 1982.
S. A. Headley, D. L. Gra？a, and I. C. Soares, “Glial fibrillary acidic protein (GFAP)—immunoreactive astrocytes in dogs infected with canine distemper virus,” Journal of Comparative Pathology, vol. 125, no. 2-3, pp. 90–97, 2001.
G. Wyss-Fluehmann, A. Zurbriggen, M. Vandevelde, and P. Plattet, “Canine distemper virus persistence in demyelinating encephalitis by swift intracellular cell-to-cell spread in astrocytes is controlled by the viral attachment protein,” Acta Neuropathologica, vol. 119, no. 5, pp. 617–630, 2010.
G. Barben, M. Stettler, A. Jaggy, M. Vandevelde, and A. Zurbriggen, “Detection of IgM antibodies against a recombinant nucleocapsid protein of canine distemper virus in dog sera using a dot-blot assay,” Journal of Veterinary Medicine, vol. 46, no. 2, pp. 115–121, 1999.
A. Tipold, P. Moore, A. Zurbriggen, I. Burgener, G. Barben, and M. Vandevelde, “Early T cell response in the central nervous system in canine distemper virus infection,” Acta Neuropathologica, vol. 97, no. 1, pp. 45–56, 1999.
C. M. S. Gebara, S. R. Wosiacki, F. J. Negr？o, D. B. de Oliveira, S. N. E. Beloni, and A. A. Alfieri, “Detection of canine distemper virus nucleoprotein gene by RT-PCR in urine of dogs with distemper clinical signs,” Arquivo Brasileiro de Medicina Veterinaria e Zootecnia, vol. 56, no. 4, pp. 480–487, 2004.
G. J. Sips, D. Chesik, L. Glazenburg, J. Wilschut, J. de Keyser, and N. Wilczak, “Involvement of morbilliviruses in the pathogenesis of demyelinating disease,” Reviews in Medical Virology, vol. 17, no. 4, pp. 223–244, 2007.
C. F. Müller, R. S. Fatzer, K. Beck, M. Vandevelde, and A. Zurbriggen, “Studies on canine distemper virus persistence in the central nervous system,” Acta Neuropathologica, vol. 89, no. 5, pp. 438–445, 1995.
W. F. Blakemore, B. A. Summers, and M. G. J. Appel, “Evidence of oligodendrocyte infection and degeneration in canine distemper encephalomyelitis,” Acta Neuropathologica, vol. 77, no. 5, pp. 550–553, 1989.
T. Glaus, C. Griot, A. Richard, U. Althaus, N. Herschkowitz, and M. Vandevelde, “Ultrastructural and biochemical findings in brain cell cultures infected with canine distemper virus,” Acta Neuropathologica, vol. 80, no. 1, pp. 59–67, 1990.
Q. Miao, W. Baumag？rtner, K. Failing, and S. Alldinger, “Phase-dependent expression of matrix metalloproteinases and their inhibitors in demyelinating canine distemper encephalitis,” Acta Neuropathologica, vol. 106, no. 5, pp. 486–494, 2003.
R. J. Higgins, G. Child, and M. Vandevelde, “Chronic relapsing demyelinating encephalomyelitis associated with persistent spontaneous canine distemper virus infection,” Acta Neuropathologica, vol. 77, no. 4, pp. 441–444, 1989.
M. Vandevelde, R. Fankhauser, F. Kristensen, and B. Kristensen, “Immunoglobulins in demyelinating lesions in canine distemper encephalitis. An immunohistological study,” Acta Neuropathologica, vol. 54, no. 1, pp. 31–41, 1981.
M. Vandevelde, R. J. Higgins, B. Kristensen, F. Kristensen, A. J. Steck, and U. Kihm, “Demyelination in experimental canine distemper virus infection: immunological, pathologic, and immunohistological studies,” Acta Neuropathologica, vol. 56, no. 4, pp. 285–293, 1982.