The mechanisms behind the virulence of immunosuppressive wild-type morbillivirus infections are still not fully understood. To investigate lymphotropism and host responses, we have selected the natural host model of canine distemper virus (CDV) infection in mink. This model displays multisystemic infection, similar to measles virus and rinderpest virus infections in their susceptible natural hosts. The wild-type CDVs investigated provoked marked virulence differences, inducing mild versus marked to severe acute disease. The mildly virulent wild-type virus induced transient lymphopenia, despite the development of massive infection of peripheral blood mononuclear cells (PBMCs) exceeding that determined for the highly virulent wild-type virus, indicating an inverse relationship between acute virulence and the extent of viraemia in the investigated wild-type viruses. Single-cell cytokine production in PBMCs was investigated throughout the acute infections. We observed Th1- and Th2-type cytokine responses beginning in the prodromal phase, and late inflammatory responses were shared between the wild-type infections.


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  1. Aasted, B., Bach, P., Nielsen, J. & Lind, P.(2002). Cytokine profiles in peripheral blood mononuclear cells and lymph node cells from piglets infected in utero with porcine reproductive and respiratory syndrome virus. Clin Diagn Lab Immunol 9, 1229–1234. [Google Scholar]
  2. Appel, M. J.(1969). Pathogenesis of canine distemper. Am J Vet Res 30, 1167–1182. [Google Scholar]
  3. Appel, M. J., Shek, W. R. & Summers, B. A.(1982). Lymphocyte-mediated immune cytotoxicity in dogs infected with virulent canine distemper virus. Infect Immun 37, 592–600. [Google Scholar]
  4. Appel, M. J., Shek, W. R., Shesberadaran, H. & Norrby, E.(1984). Measles virus and inactivated canine distemper virus induce incomplete immunity to canine distemper. Arch Virol 82, 73–82.[CrossRef] [Google Scholar]
  5. Barrett, T., Visser, I. K., Mamaev, L., Goatley, L., van Bressem, M. F. & Osterhaus, A. D.(1993). Dolphin and porpoise morbilliviruses are genetically distinct from phocine distemper virus. Virology 193, 1010–1012.[CrossRef] [Google Scholar]
  6. Blixenkrone-Møller, M.(1989). Detection of intracellular canine distemper virus antigen in mink inoculated with an attenuated or a virulent strain of canine distemper virus. Am J Vet Res 50, 1616–1620. [Google Scholar]
  7. Blixenkrone-Møller, M., Pedersen, I. R., Appel, M. J. & Griot, C.(1991). Detection of IgM antibodies against canine distemper virus in dog and mink sera employing enzyme-linked immunosorbent assay (ELISA). J Vet Diagn Invest 3, 3–9.[CrossRef] [Google Scholar]
  8. Blixenkrone-Møller, M., Svansson, V., Appel, M., Krogsrud, J., Have, P. & Örvell, C.(1992). Antigenic relationships between field isolates of morbilliviruses from different carnivores. Arch Virol 123, 279–294.[CrossRef] [Google Scholar]
  9. Blixenkrone-Møller, M., Svansson, V., Have, P., Örvell, C., Appel, M., Pedersen, I. R., Dietz, H. H. & Henriksen, P.(1993). Studies on manifestations of canine distemper virus infection in an urban dog population. Vet Microbiol 37, 163–173.[CrossRef] [Google Scholar]
  10. Bolt, G., Jensen, T. D., Gottschalck, E., Arctander, P., Appel, M. J., Buckland, R. & Blixenkrone-Møller, M.(1997). Genetic diversity of the attachment (H) protein gene of current field isolates of canine distemper virus. J Gen Virol 78, 367–372. [Google Scholar]
  11. Castelruiz, Y., Blixenkrone-Møller, M. & Aasted, B.(2005). DNA vaccination with the Aleutian mink disease virus NS1 gene confers partial protection against disease. Vaccine 23, 1225–1231.[CrossRef] [Google Scholar]
  12. Chen, W., Pedersen, M., Gram-Nielsen, S. & Aasted, B.(1997). Production and characterization of monoclonal antibodies against mink leukocytes. Vet Immunol Immunopathol 60, 161–170.[CrossRef] [Google Scholar]
  13. Condack, C., Grivel, J. C., Devaux, P., Margolis, L. & Cattaneo, R.(2007). Measles virus vaccine attenuation: suboptimal infection of lymphatic tissue and tropism alteration. J Infect Dis 196, 541–549.[CrossRef] [Google Scholar]
  14. Crook, E., Gorham, J. R. & McNutt, S. H.(1958). Experimental distemper in mink and ferret. I. Pathogenesis. Am J Vet Res 19, 955–957. [Google Scholar]
  15. Cruz, C. D., Palosaari, H., Parisien, J. P., Devaux, P., Cattaneo, R., Ouchi, T. & Horvath, C. M.(2006). Measles virus V protein inhibits p53 family member p73. J Virol 80, 5644–5650.[CrossRef] [Google Scholar]
  16. Dahl, L., Jensen, T. H., Gottschalck, E., Karlskov-Mortensen, P., Jensen, T. D., Nielsen, L., Andersen, M. K., Buckland, R., Wild, T. F. & Blixenkrone-Møller, M.(2004). Immunization with plasmid DNA encoding the hemagglutinin and the nucleoprotein confers robust protection against a lethal canine distemper virus challenge. Vaccine 22, 3642–3648.[CrossRef] [Google Scholar]
  17. Devaux, P., Hodge, G., McChesney, M. B. & Cattaneo, R.(2008). Attenuation of V- or C-defective measles viruses: infection control by the inflammatory and interferon responses of rhesus monkeys. J Virol 82, 5359–5367.[CrossRef] [Google Scholar]
  18. Egan, P. J., Rothel, J. S., Andrews, A. E., Seow, H. F., Wood, P. R. & Nash, A. D.(1994). Characterization of monoclonal antibodies to ovine tumor necrosis factor-alpha and development of a sensitive immunoassay. Vet Immunol Immunopathol 41, 259–274.[CrossRef] [Google Scholar]
  19. Fontana, J. M., Bankamp, B., Bellini, W. J. & Rota, P. A.(2008a). Regulation of interferon signaling by the C and V proteins from attenuated and wild-type strains of measles virus. Virology 374, 71–81.[CrossRef] [Google Scholar]
  20. Fontana, J. M., Bankamp, B. & Rota, P. A.(2008b). Inhibition of interferon induction and signaling by paramyxoviruses. Immunol Rev 225, 46–67.[CrossRef] [Google Scholar]
  21. Forthal, D. N., Aarnaes, S., Blanding, J., de la Maza, L. & Tilles, J. G.(1992). Degree and length of viremia in adults with measles. J Infect Dis 166, 421–424.[CrossRef] [Google Scholar]
  22. Gillespie, J. H., Baker, J. A., Burgher, J., Robson, D. & Gilman, B.(1958). The immune response of dogs to distemper virus. Cornell Vet 48, 103–126. [Google Scholar]
  23. Goodbourn, S., Didcock, L. & Randall, R. E.(2000). Interferons: cell signalling, immune modulation, antiviral response and virus countermeasures. J Gen Virol 81, 2341–2364. [Google Scholar]
  24. Greene, C. E. & Appel, M.(2006). Canine distemper. In Infectious Diseases of the Dog and Cat, pp. 25–41. Edited by C. E. Greene. St Louis, MO: Saunders Elsevier.
  25. Griffin, D. E.(2007). Measles virus. In Fields Virology, 5th edn, pp. 1551–1585. Edited by D. M. Knipe, P. M. Howley, D. E. Griffin, R. A. Lamb, M. A. Martin, B. Roizman & S. E. Straus. Philadelphia, PA: Lippincott Williams & Wilkins.
  26. Gröne, A., Frisk, A. L. & Baumgartner, W.(1998). Cytokine mRNA expression in whole blood samples from dogs with natural canine distemper virus infection. Vet Immunol Immunopathol 65, 11–27.[CrossRef] [Google Scholar]
  27. Harslund, J., Nielsen, O. L., Brunner, N. & Offenberg, H.(2007). Gender-dependent physiological implications of combined PAI-1 and TIMP-1 gene deficiency characterized in a mouse model. Am J Physiol Regul Integr Comp Physiol 293, R1630–R1639.[CrossRef] [Google Scholar]
  28. Heaney, J., Barrett, T. & Cosby, S. L.(2002). Inhibition of in vitro leukocyte proliferation by morbilliviruses. J Virol 76, 3579–3584.[CrossRef] [Google Scholar]
  29. Heaney, J., Cosby, S. L. & Barrett, T.(2005). Inhibition of host peripheral blood mononuclear cell proliferation ex vivo by Rinderpest virus. J Gen Virol 86, 3349–3355.[CrossRef] [Google Scholar]
  30. Jensen, P. V., Castelruiz, Y. & Aasted, B.(2003). Cytokine profiles in adult mink infected with Aleutian mink disease parvovirus. J Virol 77, 7444–7451.[CrossRef] [Google Scholar]
  31. Karp, C. L., Wysocka, M., Wahl, L. M., Ahearn, J. M., Cuomo, P. J., Sherry, B., Trinchieri, G. & Griffin, D. E.(1996). Mechanism of suppression of cell-mediated immunity by measles virus. Science 273, 228–231.[CrossRef] [Google Scholar]
  32. Kauffman, C. A., Bergman, A. G. & O'Connor, R. P.(1982). Distemper virus infection in ferrets: an animal model of measles-induced immunosuppression. Clin Exp Immunol 47, 617–625. [Google Scholar]
  33. Krakowka, S. & Koestner, A.(1977). Comparison of canine distemper virus strains in gnotobiotic dogs: effects on lymphoid tissues. Am J Vet Res 38, 1919–1922. [Google Scholar]
  34. Krakowka, S., Higgins, R. J. & Koestner, A.(1980). Canine distemper virus: review of structural and functional modulations in lymphoid tissues. Am J Vet Res 41, 284–292. [Google Scholar]
  35. Martella, V., Cirone, F., Elia, G., Lorusso, E., Decaro, N., Campolo, M., Desario, C., Lucente, M. S., Bellacicco, A. L. & other authors(2006). Heterogeneity within the hemagglutinin genes of canine distemper virus (CDV) strains detected in Italy. Vet Microbiol 116, 301–309.[CrossRef] [Google Scholar]
  36. Nakatsu, Y., Takeda, M., Ohno, S., Shirogane, Y., Iwasaki, M. & Yanagi, Y.(2008). Measles virus circumvents the host interferon response by different actions of the C and V proteins. J Virol 82, 8296–8306.[CrossRef] [Google Scholar]
  37. Örvell, C., Sheshberadaran, H. & Norrby, E.(1985). Preparation and characterization of monoclonal antibodies directed against four structural components of canine distemper virus. J Gen Virol 66, 443–456.[CrossRef] [Google Scholar]
  38. Pearson, C. R. & Gorham, J. R.(1987). Canine distemper virus. In Virus Infections of Carnivores, pp. 371–383. Edited by M. Appel. Amsterdam: Elsevier.
  39. Pedersen, L. G., Castelruiz, Y., Jacobsen, S. & Aasted, B.(2002). Identification of monoclonal antibodies that cross-react with cytokines from different animal species. Vet Immunol Immunopathol 88, 111–122.[CrossRef] [Google Scholar]
  40. Reed, L. J. & Muench, H. A.(1938). A simple method of estimating fifty per cent endpoints. Am J Hyg 27, 493–497. [Google Scholar]
  41. Rima, B. K. & Duprex, W. P.(2006). Morbilliviruses and human disease. J Pathol 208, 199–214.[CrossRef] [Google Scholar]
  42. Schlender, J., Schnorr, J. J., Spielhoffer, P., Cathomen, T., Cattaneo, R., Billeter, M. A., ter Meulen, V. & Schneider-Schaulies, S.(1996). Interaction of measles virus glycoproteins with the surface of uninfected peripheral blood lymphocytes induces immunosuppression in vitro. Proc Natl Acad Sci U S A 93, 13194–13199.[CrossRef] [Google Scholar]
  43. Schneider-Schaulies, S. & Dittmer, U.(2006). Silencing T cells or T-cell silencing: concepts in virus-induced immunosuppression. J Gen Virol 87, 1423–1438.[CrossRef] [Google Scholar]
  44. Seki, F., Ono, N., Yamaguchi, R. & Yanagi, Y.(2003). Efficient isolation of wild strains of canine distemper virus in Vero cells expressing canine SLAM (CD150) and their adaptability to marmoset B95a cells. J Virol 77, 9943–9950.[CrossRef] [Google Scholar]
  45. Stephensen, C. B., Welter, J., Thaker, S. R., Taylor, J., Tartaglia, J. & Paoletti, E.(1997). Canine distemper virus (CDV) infection of ferrets as a model for testing Morbillivirus vaccine strategies: NYVAC- and ALVAC-based CDV recombinants protect against symptomatic infection. J Virol 71, 1506–1513. [Google Scholar]
  46. Summers, B. A., Greisen, H. A. & Appel, M. J.(1984). Canine distemper encephalomyelitis: variation with virus strain. J Comp Pathol 94, 65–75.[CrossRef] [Google Scholar]
  47. Svitek, N. & von Messling, V.(2007). Early cytokine mRNA expression profiles predict morbillivirus disease outcome in ferrets. Virology 362, 404–410.[CrossRef] [Google Scholar]
  48. Takeuchi, K., Takeda, M., Miyajima, N., Ami, Y., Nagata, N., Suzaki, Y., Shahnewaz, J., Kadota, S. & Nagata, K.(2005). Stringent requirement for the C protein of wild-type measles virus for growth both in vitro and in macaques. J Virol 79, 7838–7844.[CrossRef] [Google Scholar]
  49. Tatsuo, H., Ono, N. & Yanagi, Y.(2001). Morbilliviruses use signaling lymphocyte activation molecules (CD150) as cellular receptors. J Virol 75, 5842–5850.[CrossRef] [Google Scholar]
  50. von Messling, V., Springfeld, C., Devaux, P. & Cattaneo, R.(2003). A ferret model of canine distemper virus virulence and immunosuppression. J Virol 77, 12579–12591.[CrossRef] [Google Scholar]
  51. von Messling, V., Svitek, N. & Cattaneo, R.(2006). Receptor (SLAM [CD150]) recognition and the V protein sustain swift lymphocyte-based invasion of mucosal tissue and lymphatic organs by a morbillivirus. J Virol 80, 6084–6092.[CrossRef] [Google Scholar]
  52. Yanagi, Y., Takeda, M. & Ohno, S.(2006). Measles virus: cellular receptors, tropism and pathogenesis. J Gen Virol 87, 2767–2779.[CrossRef] [Google Scholar]

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