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

Lab Animal volume 42, pages 170176 (2013) | Download Citation

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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. 1.

    , , , & The cotton rat in biomedical research. Lab Anim. Sci. 47, 337–345 (1997).

  2. 2.

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

  3. 3.

    & 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).

  4. 4.

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

  5. 5.

    , & The cotton rat model of respiratory viral infections. Biologicals 37, 152–159 (2009).

  6. 6.

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

  7. 7.

    & Measles virus neurovirulence and host immunity. Future Virol. 6, 85–99 (2011).

  8. 8.

    & 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).

  9. 9.

    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).

  10. 10.

    , & Animal models of human respiratory syncytial virus disease. Am. J. Physiol. Lung Cell Mol. Physiol. 301, L148–L156 (2011).

  11. 11.

    , , , & New insights for development of a safe and protective RSV vaccine. Hum. Vaccin. 6, 482–492 (2010).

  12. 12.

    , , & Immunity to and frequency of reinfection with respiratory syncytial virus. J. Infect. Dis. 163, 693–698 (1991).

  13. 13.

    , & Serum antibody decay in adults following natural respiratory syncytial virus infection. J. Med. Virol. 78, 1493–1497 (2006).

  14. 14.

    , , , & Respiratory syncytial virus infection in elderly and high-risk adults. N. Engl. J. Med. 352, 1749–1759 (2005).

  15. 15.

    & Respiratory syncytial virus infection in adult populations. Infect. Disord. Drug Targets 12, 98–102 (2012).

  16. 16.

    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).

  17. 17.

    , , & 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).

  18. 18.

    , , , & Mechanisms of immunity to respiratory syncytial virus in cotton rats. Infect. Immun. 42, 81–87 (1983).

  19. 19.

    , , & Age-dependent replication of respiratory syncytial virus in the cotton rat. Exp. Biol. Med. 227, 799–802 (2002).

  20. 20.

    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).

  21. 21.

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

  22. 22.

    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).

  23. 23.

    , , & Sialic acid recognition is a key determinant of influenza A virus tropism in murine trachea epithelial cell cultures. Virology 386, 61–67 (2009).

  24. 24.

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

  25. 25.

    , , , & Interferon-inducible Mx gene expression in cotton rats: cloning, characterization, and expression during influenza viral infection. J. Interferon Cytokine Res. 26, 914–921 (2006).

  26. 26.

    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).

  27. 27.

    , , & Comparison of airway measurements during influenza-induced tachypnea in infant and adult cotton rats. BMC Pulm. Med. 9, 28 (2009).

  28. 28.

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

  29. 29.

    , , & Evidence of a cross-protective immune response to influenza A in the cotton rat model. Vaccine 24, 6264–6271 (2006).

  30. 30.

    , , & Antibody contributes to heterosubtypic protection against influenza A-induced tachypnea in cotton rats. Virol. J. 5, 44 (2008).

  31. 31.

    , , & 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).

  32. 32.

    , , & A cotton rat model of human parainfluenza 3 laryngotracheitis: virus growth, pathology, and therapy. J. Infect. Dis. 186, 1713–1717 (2002).

  33. 33.

    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).

  34. 34.

    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).

  35. 35.

    & 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).

  36. 36.

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

  37. 37.

    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).

  38. 38.

    , , , & 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).

  39. 39.

    , & 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).

  40. 40.

    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).

  41. 41.

    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).

  42. 42.

    , , & 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).

  43. 43.

    , , & 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).

  44. 44.

    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).

  45. 45.

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

  46. 46.

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

  47. 47.

    , , , & Development of a cotton rat-human metapneumovirus (hMPV) model for identifying and evaluating potential hMPV antivirals and vaccines. Antiviral Res. 2005, 57–66 (2005).

  48. 48.

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

  49. 49.

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

  50. 50.

    , & Nutritional requirements for reproduction in the hispid cotton rat, Sigmodon hispidus. J. Mammal. 76, 1113–1126 (1995).

  51. 51.

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

  52. 52.

    , & A maintenance and handling device for cotton rats (Sigmodon hispidus). Lab Anim. (NY) 26, 32–33 (1997).

  53. 53.

    & Development and management of a cotton rat colony. Am. J. Public Health Nations Health 33, 697–700 (1943).

  54. 54.

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

  55. 55.

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

  56. 56.

    , , & 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).

  57. 57.

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

  58. 58.

    , , , & 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).

  59. 59.

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

  60. 60.

    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).

  61. 61.

    & 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).

  62. 62.

    , , & Insights into the regulatory mechanism controlling the inhibition of vaccine-induced seroconversion by maternal antibodies. Blood 117, 6143–6151 (2011).

  63. 63.

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

  64. 64.

    , , , & Measles virus-specific CD4 T-cell activity does not correlate with protection against lung infection or viral clearance. J. Virol. 81, 8571–8578 (2007).

  65. 65.

    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).

  66. 66.

    , , & Induction of mucosal immunity in cotton rats to haemagglutinin-esterase glycoprotein of bovine coronavirus by recombinant adenovirus. Immunology 86, 134–140 (1995).

  67. 67.

    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).

  68. 68.

    , , & 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).

  69. 69.

    , & Selective in vivo suppression of T lymphocyte responses in experimental measles virus infection. Proc. Natl. Acad. Sci. USA 74, 4652–4657 (2000).

  70. 70.

    , , & 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).

  71. 71.

    , , , & High in vitro endotoxin responsiveness of macrophages from an endotoxin-resistant wild rodent species, Sigmodon hispidus. Dev. Comp. Immunol. 18, 147–153 (1994).

  72. 72.

    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).

  73. 73.

    , , , & 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).

  74. 74.

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

  75. 75.

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

  76. 76.

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

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Affiliations

  1. Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH.

    • M. Gia Green
    • , Devra Huey
    •  & Stefan Niewiesk

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The authors declare no competing financial interests.

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Correspondence to Stefan Niewiesk.

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DOI

https://doi.org/10.1038/laban.188