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The cotton rat (Sigmodon hispidus) as an animal model for respiratory tract infections with human pathogens

Abstract

Respiratory viral infection is a great human health concern, resulting in disease, death and economic losses. Cotton rats (Sigmodon hispidus) have been particularly useful in the study of the pathogenesis of human respiratory virus infections, including the development and testing of antiviral compounds and vaccines. In this article, the authors outline the advantages of the cotton rat compared with the mouse as a model for infection with measles virus, respiratory syncytial virus, influenza virus, human parainfluenza virus and human metapneumovirus. From the literature and their own experience, the authors summarize guidelines for handling, maintaining and breeding cotton rats. In addition, they offer technical tips for carrying out infection experiments and provide information about the large array of immunological assays and reagents available for the study of immune responses (macrophages, dendritic cells, T cells, B cells, antibodies, chemokines and cytokines) in cotton rats.

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References

  1. Faith, R.E., Montgomery, C.A., Durfee, W.J., Aguilar-Cordova, E. & Wyde, P.R. The cotton rat in biomedical research. Lab Anim. Sci. 47, 337–345 (1997).

    CAS  PubMed  Google Scholar 

  2. Niewiesk, S. & Prince, G.A. Diversifying animal models: the use of hispid cotton rats (Sigmodon hispidus) in infectious diseases. Lab. Anim. 36, 357–372 (2002).

    Article  CAS  Google Scholar 

  3. Cameron, G.N. & McClure, P.A. Geographic variation in life history traits of the hispid cotton rat (Sigmodon hispidus). in Evolution of Life Histories of Mammals (ed. Boyce, M.S.) 33–64 (Yale University Press, New Haven, CT, 1988).

    Google Scholar 

  4. Armstrong, C. The experimental transmission of poliomyelitis to the eastern cotton rat Sigmodon hispidus hispidus. Public Health Rep. 54, 1719–1721 (1939).

    Article  Google Scholar 

  5. Boukhvalova, M.S., Prince, G.A. & Blanco, J.C. The cotton rat model of respiratory viral infections. Biologicals 37, 152–159 (2009).

    Article  CAS  Google Scholar 

  6. Meyer, B.J. & Meyer, R.K. Growth and reproduction of the cotton rat, Sigmodon hispidus hispidus, under laboratory conditions. J. Mammal. 25, 107–129 (1944).

    Article  Google Scholar 

  7. Oglesbee, M. & Niewiesk, S. Measles virus neurovirulence and host immunity. Future Virol. 6, 85–99 (2011).

    Article  CAS  Google Scholar 

  8. Sellin, C.I. & Horvat, B. Current animal models: transgenic animal models for the study of measles pathogenesis. in Measles - Pathogenesis and Control vol. 330 (eds. Griffin, D.E. & Oldstone, M.B.A.) 111–128 (Springer, Heidelberg, 2008).

    Google Scholar 

  9. Niewiesk, S. Current animal models: cotton rat. in Measles - Pathogenesis and Control vol. 330 (eds. Griffin, D.E. & Oldstone, M.B.A.) 89–110 (Springer, Heidelberg, 2009).

    Google Scholar 

  10. Bem, R.A., Domachowske, J.B. & Rosenberg, H.F. Animal models of human respiratory syncytial virus disease. Am. J. Physiol. Lung Cell Mol. Physiol. 301, L148–L156 (2011).

    Article  CAS  Google Scholar 

  11. Blanco, J.C., Boukhvalova, M.S., Shirey, K.A., Prince, G.A. & Vogel, S.N. New insights for development of a safe and protective RSV vaccine. Hum. Vaccin. 6, 482–492 (2010).

    Article  CAS  Google Scholar 

  12. Hall, C.B., Walsh, E.E., Long, C.E. & Schnabel, K.C. Immunity to and frequency of reinfection with respiratory syncytial virus. J. Infect. Dis. 163, 693–698 (1991).

    Article  CAS  Google Scholar 

  13. Falsey, A.R., Singh, H.K. & Walsh, E.E. Serum antibody decay in adults following natural respiratory syncytial virus infection. J. Med. Virol. 78, 1493–1497 (2006).

    Article  CAS  Google Scholar 

  14. Falsey, A.R., Hennessey, P.A., Formica, M.A., Cox, C. & Walsh, E.E. Respiratory syncytial virus infection in elderly and high-risk adults. N. Engl. J. Med. 352, 1749–1759 (2005).

    Article  CAS  Google Scholar 

  15. Walsh, E.E. & Falsey, A.R. Respiratory syncytial virus infection in adult populations. Infect. Disord. Drug Targets 12, 98–102 (2012).

    Article  CAS  Google Scholar 

  16. Prince, G.A. et al. Enhancement of respiratory syncytial virus pulmonary pathology in cotton rats by prior intramuscular inoculation of formalin-inactivated virus. J. Virol. 57, 721–728 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Prince, G.A., Curtis, S.J., Yim, K.C. & Porter, D.D. Vaccine-enhanced respiratory syncytial virus disease in cotton rats following immunization with Lot 100 or a newly prepared reference vaccine. J. Gen. Virol. 82, 2881–2888 (2001).

    Article  CAS  Google Scholar 

  18. Prince, G.A., Horswood, R.L., Camargo, E., Koenig, D. & Chanock, R.M. Mechanisms of immunity to respiratory syncytial virus in cotton rats. Infect. Immun. 42, 81–87 (1983).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Curtis, S.J., Ottolini, M.G., Porter, D.D. & Prince, G.A. Age-dependent replication of respiratory syncytial virus in the cotton rat. Exp. Biol. Med. 227, 799–802 (2002).

    Article  CAS  Google Scholar 

  20. Boukhvalova, M.S. et al. Age-related differences in pulmonary cytokine response to respiratory syncytial virus infection: modulation by anti-inflammatory and antiviral treatment. J. Infect. Dis. 195, 511–518 (2007).

    Article  CAS  Google Scholar 

  21. Prince, G.A. The cotton rat in biomedical research. AWIC Newsletter 5, 3–5 (1994).

    Google Scholar 

  22. Wu, H. et al. Development of motavizumab, an ultra-potent antibody for the prevention of respiratory syncytial virus infection in the upper and lower respiratory tract. J. Mol. Biol. 368, 652–665 (2007).

    Article  CAS  Google Scholar 

  23. Pekosz, A., Newby, C., Bose, P.S. & Lutz, A. Sialic acid recognition is a key determinant of influenza A virus tropism in murine trachea epithelial cell cultures. Virology 386, 61–67 (2009).

    Article  CAS  Google Scholar 

  24. Eichelberger, M.C. The cotton rat as a model to study influenza pathogenesis and immunity. Viral Immunol. 20, 243–249 (2007).

    Article  CAS  Google Scholar 

  25. Pletneva, L.M., Haller, O., Porter, D.D., Prince, G.A. & Blanco, J.C. Interferon-inducible Mx gene expression in cotton rats: cloning, characterization, and expression during influenza viral infection. J. Interferon Cytokine Res. 26, 914–921 (2006).

    Article  CAS  Google Scholar 

  26. Stertz, S. et al. The antiviral potential of interferon-induced cotton rat mx proteins against orthomyxovirus (influenza), rhabdovirus, and bunyavirus. J. Interferon Cytokine Res. 27, 847–855 (2007).

    Article  CAS  Google Scholar 

  27. Trias, E.L., Hassantoufighi, A., Prince, G.A. & Eichelberger, M.C. Comparison of airway measurements during influenza-induced tachypnea in infant and adult cotton rats. BMC Pulm. Med. 9, 28 (2009).

    Article  Google Scholar 

  28. Eichelberger, M.C. et al. Distinct cellular immune responses following primary and secondary influenza virus challenge in cotton rats. Cell Immunol. 243, 67–74 (2006).

    Article  CAS  Google Scholar 

  29. Straight, T.M., Ottolini, M.G., Prince, G.A. & Eichelberger, M.C. Evidence of a cross-protective immune response to influenza A in the cotton rat model. Vaccine 24, 6264–6271 (2006).

    Article  CAS  Google Scholar 

  30. Straight, T.M., Ottolini, M.G., Prince, G.A. & Eichelberger, M.C. Antibody contributes to heterosubtypic protection against influenza A-induced tachypnea in cotton rats. Virol. J. 5, 44 (2008).

    Article  Google Scholar 

  31. Porter, D.D., Prince, G.A., Hemming, V.G. & Porter, H.G. Pathogenesis of human parainfluenza virus 3 infection in two species of cotton rats: Sigmodon hispidus develops bronchiolitis, while Sigmodon fulviventer develops interstitial pneumonia. J. Virol. 65, 103–111 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Ottolini, M.G., Porter, D.D., Blanco, J.C. & Prince, G.A. A cotton rat model of human parainfluenza 3 laryngotracheitis: virus growth, pathology, and therapy. J. Infect. Dis. 186, 1713–1717 (2002).

    Article  Google Scholar 

  33. Palermo, L.M. et al. Human parainfluenza virus infection of the airway epithelium: viral hemagglutinin-neuraminidase regulates fusion protein activation and modulates infectivity. J. Virol. 83, 6900–6908 (2009).

    Article  CAS  Google Scholar 

  34. Moscona, A. et al. A recombinant sialidase fusion protein effectively inhibits human parainfluenza viral infection in vitro and in vivo. J. Infect. Dis. 202, 234–241 (2010).

    Article  CAS  Google Scholar 

  35. Prince, G.A. & Porter, D.D. Treatment of parainfluenza virus type 3 bronchiolitis and pneumonia in a cotton rat model using topical antibody and glucocorticosteroid. J. Infect. Dis. 173, 598–608 (1996).

    Article  CAS  Google Scholar 

  36. Ottolini, M.G. et al. Topical immunoglobulin is an effective therapy for parainfluenza type 3 in a cotton rat model. J. Infect. Dis. 172, 243–245 (1995).

    Article  CAS  Google Scholar 

  37. Breker-Klassen, M.M. et al. Recombinant type 5 adenoviruses expressing bovine parainfluenza virus type 3 glycoproteins protect Sigmodon hispidus cotton rats from bovine parainfluenza virus type 3 infection. J. Virol. 69, 4308–4315 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Brideau, R.J., Oien, N.L., Lehman, D.J., Homa, F.L. & Wathen, M.W. Protection of cotton rats against human parainfluenza virus type 3 by vaccination with a chimeric FHN subunit glycoprotein. J. Gen. Virol. 74, 471–477 (1993).

    Article  CAS  Google Scholar 

  39. Hall, S.L., Murphy, B.R. & van Wyke Coelingh, K.L. Protection of cotton rats by immunization with the human parainfluenza virus type 3 fusion (F) glycoprotein expressed on the surface of insect cells infected with a recombinant baculovirus. Vaccine 9, 659–667 (1991).

    Article  CAS  Google Scholar 

  40. Ambrose, M.W. et al. Evaluation of the immunogenicity and protective efficacy of a candidate parainfluenza virus type 3 subunit vaccine in cotton rats. Vaccine 9, 505–511 (1991).

    Article  CAS  Google Scholar 

  41. Jones, B. et al. Human PIV-2 recombinant Sendai virus (rSeV) elicits durable immunity and combines with two additional rSeVs to protect against hPIV-1, hPIV-2, hPIV-3, and RSV. Vaccine 27, 1848–1857 (2009).

    Article  CAS  Google Scholar 

  42. Sealy, R., Jones, B.G., Surman, S.L. & Hurwitz, J.L. Robust IgA and IgG-producing antibody forming cells in the diffuse-NALT and lungs of Sendai virus-vaccinated cotton rats associate with rapid protection against human parainfluenza virus-type 1. Vaccine 28, 6749–6756 (2010).

    Article  CAS  Google Scholar 

  43. Williams, J.V., Tollefson, S.J., Johnson, J.E. & Crowe, J.E. Jr. The cotton rat (Sigmodon hispidus) is a permissive small animal model of human metapneumovirus infection, pathogenesis, and protective immunity. J. Virol. 79, 10944–10951 (2005).

    Article  CAS  Google Scholar 

  44. Williams, J.V. et al. A recombinant human monoclonal antibody to human metapneumovirus fusion protein that neutralizes virus in vitro and is effective therapeutically in vivo. J. Virol. 81, 8315–8324 (2007).

    Article  CAS  Google Scholar 

  45. Mok, H. et al. An alphavirus replicon-based human metapneumovirus vaccine is immunogenic and protective in mice and cotton rats. J. Virol. 82, 11410–11418 (2008).

    Article  CAS  Google Scholar 

  46. Cseke, G. et al. Human metapneumovirus fusion protein vaccines that are immunogenic and protective in cotton rats. J. Virol. 81, 698–707 (2007).

    Article  CAS  Google Scholar 

  47. Wyde, P.R., Chetty, S.N., Jewell, A.M., Schoonover, S.L. & Piedra, P.A. Development of a cotton rat-human metapneumovirus (hMPV) model for identifying and evaluating potential hMPV antivirals and vaccines. Antiviral Res. 2005, 57–66 (2005).

    Article  Google Scholar 

  48. Hamelin, M.E. et al. Pathogenesis of human metapneumovirus lung infection in BALB/c mice and cotton rats. J. Virol. 79, 8894–8903 (2005).

    Article  CAS  Google Scholar 

  49. Animal Welfare Act as Amended (7 USC 2131-2156).

  50. Randolph, J.C., Cameron, G.N. & McClure, P.A. Nutritional requirements for reproduction in the hispid cotton rat, Sigmodon hispidus. J. Mammal. 76, 1113–1126 (1995).

    Article  Google Scholar 

  51. Ward, L.E. Handling the cotton rat for research. Lab Anim. (NY). 30, 45–50 (2001).

    CAS  PubMed  Google Scholar 

  52. Niewiesk, S., Völp, F. & ter Meulen, V. A maintenance and handling device for cotton rats (Sigmodon hispidus). Lab Anim. (NY) 26, 32–33 (1997).

    Google Scholar 

  53. Meyer, D.B. & Marsh, M. Development and management of a cotton rat colony. Am. J. Public Health Nations Health 33, 697–700 (1943).

    Article  CAS  Google Scholar 

  54. Goertz, J.W. Reproductive variation in cotton rats. American Midland Naturalist 74, 329–340 (1965).

    Article  Google Scholar 

  55. Johston, P.G. & Zucker, I. Photoperiodic influences on gonadal development and maintenance in the cotton rat, Sigmodon hispidus. Biol. Reprod. 21, 1–8 (1979).

    Article  Google Scholar 

  56. Gupta, C.K., Leszczynski, J., Gupta, R.K. & Siber, G.R. Stabilization of respiratory syncytial virus (RSV) against thermal inactivation and freeze-thaw cycles for development and control of RSV vaccines and immune globulin. Vaccine 14, 1417–1420 (1996).

    Article  CAS  Google Scholar 

  57. Elwood, R.L. et al. The American cotton rat: a novel model for pulmonary tuberculosis. Tuberculosis 87, 145–154 (2007).

    Article  CAS  Google Scholar 

  58. Richter, B.W., Onuska, J.M., Niewiesk, S., Prince, G.A. & Eichelberger, M.C. Antigen-dependent proliferation and cytokine induction in respiratory syncytial virus-infected cotton rats reflect the presence of effector-memory T cells. Virology 337, 102–110 (2005).

    Article  CAS  Google Scholar 

  59. Streif, S. et al. Effector CD8+T cells are suppressed by measles virus infection during delayed type hypersensitivity reaction. Viral Immunol. 17, 604–608 (2004).

    Article  CAS  Google Scholar 

  60. Carsillo, M. et al. Nitric oxide production and nitric oxide synthase type 2 expression by cotton rat (Sigmodon hispidus) macrophages reflect the same pattern as human macrophages. Dev. Comp. Immunol. 33, 718–724 (2009).

    Article  CAS  Google Scholar 

  61. Kim, D. & Niewiesk, S. Synergistic induction of interferon α through TLR-3 and TLR-9 agonists identifies CD21 as interferon α receptor for the B cell response. PLoS Pathogens 9, e1003233 (2013).

    Article  CAS  Google Scholar 

  62. Kim, D., Huey, D., Oglesbee, M. & Niewiesk, S. Insights into the regulatory mechanism controlling the inhibition of vaccine-induced seroconversion by maternal antibodies. Blood 117, 6143–6151 (2011).

    Article  CAS  Google Scholar 

  63. Schachtner, S.K. et al. In vivo adenovirus-mediated gene transfer via the pulmonary artery of rats. Circ. Res. 76, 701–709 (1995).

    Article  CAS  Google Scholar 

  64. Pueschel, K., Tietz, A., Carsillo, M., Steward, M. & Niewiesk, S. Measles virus-specific CD4 T-cell activity does not correlate with protection against lung infection or viral clearance. J. Virol. 81, 8571–8578 (2007).

    Article  CAS  Google Scholar 

  65. Schlereth, B. et al. Successful mucosal immunization of cotton rats in the presence of measles virus-specific antibodies depends on degree of attenuation of vaccine vector and virus dose. J. Gen. Virol. 84, 2145–2151 (2003).

    Article  CAS  Google Scholar 

  66. Baca-Estrada, M.E., Liang, X., Babiuk, L.A. & Yoo, D. Induction of mucosal immunity in cotton rats to haemagglutinin-esterase glycoprotein of bovine coronavirus by recombinant adenovirus. Immunology 86, 134–140 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Zhan, X. et al. Respiratory syncytial virus (RSV) fusion protein expressed by recombinant Sendai virus elicits B-cell and T-cell responses in cotton rats and confers protection against RSV subtypes A and B. Vaccine 25, 8782–8793 (2007).

    Article  CAS  Google Scholar 

  68. McMurry, S.T., Lochmiller, R.L., Chandra, S.A.M. & Qualls, C.W. Sensitivity of selected immunological, hematological, and reproductive parameters in the cotton rat (Sigmodon hispidus) to subchronic lead exposure. J. Wild. Dis. 31, 193–204 (1995).

    Article  CAS  Google Scholar 

  69. Niewiesk, S., Götzelmann, M. & ter Meulen, V. Selective in vivo suppression of T lymphocyte responses in experimental measles virus infection. Proc. Natl. Acad. Sci. USA 74, 4652–4657 (2000).

    Google Scholar 

  70. Sealy, R., Jones, B.G., Surman, S.L. & Hurwitz, J.L. Robust IgA and IgG-producing antibody forming cells in the diffuse-NALT and lungs of Sendai virus-vaccinated cotton rats associate with rapid protection against human parainfluenza virus-type 1. Vaccine 28, 6749–6756 (2010).

    Article  CAS  Google Scholar 

  71. Dabbert, C.B., Lochmiller, R.L., Zhang, J.R., Qualls, C.W. & Burnham, K.B. High in vitro endotoxin responsiveness of macrophages from an endotoxin-resistant wild rodent species, Sigmodon hispidus. Dev. Comp. Immunol. 18, 147–153 (1994).

    Article  CAS  Google Scholar 

  72. Kim, D. et al. Induction of type I interferon secretion through recombinant Newcastle disease virus expressing measles virus hemagglutinin stimulates antibody secretion in the presence of maternal antibodies. J. Virol. 85, 200–207 (2011).

    Article  CAS  Google Scholar 

  73. Pletneva, L.M., Haller, O., Porter, D.D., Prince, G.A. & Blanco, J.C. Induction of type I interferons and interferon-inducible Mx genes during respiratory syncytial virus infection and reinfection in cotton rats. J. Gen. Virol. 89, 261–270 (2008).

    Article  CAS  Google Scholar 

  74. Niewiesk, S. et al. Measles virus-induced immune suppression in the cotton rat (Sigmodon hispidus) model depends on viral glycoproteins. J. Virol. 71, 7214–7219 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Ohwada, K., Ito, T. & Katahira, K. Reference values for blood chemistry in the cotton rat (Sigmodon hispidus). Scand. J. Lab Anim. Sci. 21, 29–31 (1994).

    Google Scholar 

  76. Katahira, K. & Ohwada, K. Hematological standard values in the cotton rat (Sigmodon hispidus). Exp. Anim. 42, 653–655 (1993).

    Article  CAS  Google Scholar 

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Green, M., Huey, D. & Niewiesk, S. The cotton rat (Sigmodon hispidus) as an animal model for respiratory tract infections with human pathogens. Lab Anim 42, 170–176 (2013). https://doi.org/10.1038/laban.188

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