Rodent Models of Congenital Cytomegalovirus Infection

  • Djurdjica Cekinovic
  • Vanda Juranic Lisnic
  • Stipan JonjicEmail author
Part of the Methods in Molecular Biology book series (MIMB, volume 1119)


Human cytomegalovirus (HCMV) is a leading viral cause of congenital infections in the central nervous system (CNS) and may result in severe long-term sequelae. High rates of sequelae following congenital HCMV infection and insufficient antiviral therapy in the perinatal period make the development of an HCMV-specific vaccine a high priority of modern medicine. Due to species specificity of HCMV, animal models are frequently used to study CMV pathogenesis. Studies of murine cytomegalovirus (MCMV) infections of adult mice have served a major role as a model of CMV biology and pathogenesis, while MCMV infection of newborn mice has been successfully used as a model of perinatal CMV infection. Newborn mice infected with MCMV have high levels of viremia during which the virus establishes productive infection in most organs, coupled with a strong inflammatory response. Productive infection in the brain parenchyma during early postnatal period leads to an extensive non-necrotizing multifocal widespread encephalitis characterized by infiltration of components of both innate and adaptive immunity. As a result, impairment in postnatal development of mouse cerebellum leads to long-term motor and sensor disabilities. This chapter summarizes current findings of rodent models of perinatal CMV infection and describes methods for analysis of perinatal MCMV infection in newborn mice.

Key words

Cytomegalovirus Brain Congenital infections 


  1. 1.
    Britt W (2010) Cytomegalovirus. In: Remington JS et al (eds) Infectious diseases of the fetus and newborn infant. Elsevier, Philadelphia, pp 706–756Google Scholar
  2. 2.
    Cannon MJ (2009) Congenital cytomegalovirus (CMV) epidemiology and awareness. J Clin Virol 46(Suppl 4):S6–S10PubMedCrossRefGoogle Scholar
  3. 3.
    Becroft DMO (1981) Prenatal cytomegalovirus infection: epidemiology, pathology and pathogenesis. In: Rosenberg HS, Bernstein J (eds) Perspective in pediatric pathology. Masson, New York, pp 203–241Google Scholar
  4. 4.
    Morton CC, Nance WE (2006) Newborn hearing screening – a silent revolution. N Engl J Med 354(20):2151–2164PubMedCrossRefGoogle Scholar
  5. 5.
    Kenneson A, Cannon MJ (2007) Review and meta-analysis of the epidemiology of congenital cytomegalovirus (CMV) infection. Rev Med Virol 17(4):253–276PubMedCrossRefGoogle Scholar
  6. 6.
    Ross SA, Boppana SB (2005) Congenital cytomegalovirus infection: outcome and diagnosis. Semin Pediatr Infect Dis 16(1):44–49PubMedCrossRefGoogle Scholar
  7. 7.
    Cheeran MC, Lokensgard JR, Schleiss MR (2009) Neuropathogenesis of congenital cytomegalovirus infection: disease mechanisms and prospects for intervention. Clin Microbiol Rev 22(1):99–126, Table of ContentsPubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Griffith BP, Lucia HL, Hsiung GD (1982) Brain and visceral involvement during congenital cytomegalovirus infection of guinea pigs. Pediatr Res 16(6):455–459PubMedCrossRefGoogle Scholar
  9. 9.
    Keithley EM, Woolf NK, Harris JP (1989) Development of morphological and physiological changes in the cochlea induced by cytomegalovirus. Laryngoscope 99(4):409–414PubMedCrossRefGoogle Scholar
  10. 10.
    Streblow DN et al (2008) Mechanisms of cytomegalovirus-accelerated vascular disease: induction of paracrine factors that promote angiogenesis and wound healing. Curr Top Microbiol Immunol 325:397–415PubMedCentralPubMedGoogle Scholar
  11. 11.
    Priscott PK, Tyrrell DA (1982) The isolation and partial characterisation of a cytomegalovirus from the brown rat, Rattus norvegicus. Arch Virol 73(2):145–160PubMedCrossRefGoogle Scholar
  12. 12.
    Loh HS et al (2003) Characterization of a novel rat cytomegalovirus (RCMV) infecting placenta-uterus of Rattus rattus diardii. Arch Virol 148(12):2353–2367PubMedCrossRefGoogle Scholar
  13. 13.
    Loh HS et al (2006) Pathogenesis and vertical transmission of a transplacental rat cytomegalovirus. Virol J 3:42PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Li L et al (2008) Induction of cytomegalovirus-infected labyrinthitis in newborn mice by lipopolysaccharide: a model for hearing loss in congenital CMV infection. Lab Invest 88(7):722–730PubMedCrossRefGoogle Scholar
  15. 15.
    Ishiwata M et al (2006) Differential expression of the immediate-early 2 and 3 proteins in developing mouse brains infected with murine cytomegalovirus. Arch Virol 151(11):2181–2196PubMedCrossRefGoogle Scholar
  16. 16.
    Tsutsui Y (2009) Effects of cytomegalovirus infection on embryogenesis and brain development. Congenit Anom (Kyoto) 49(2):47–55CrossRefGoogle Scholar
  17. 17.
    Koontz T et al (2008) Altered development of the brain after focal herpesvirus infection of the central nervous system. J Exp Med 205(2):423–435PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Wu CA et al (2011) Transmission of murine cytomegalovirus in breast milk: a model of natural infection in neonates. J Virol 85(10):5115–5124PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Kosugi I et al (2002) Innate immune responses to cytomegalovirus infection in the developing mouse brain and their evasion by virus-infected neurons. Am J Pathol 161(3):919–928PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    van Den Pol AN et al (1999) Cytomegalovirus cell tropism, replication, and gene transfer in brain. J Neurosci 19(24):10948–10965Google Scholar
  21. 21.
    Stagno S, Britt WJ (2006) Cytomegalovirus. In: Remington JS, Klein JO (eds) Diseases of the fetus and newborn infant. Saunders, Philadelphia, PAGoogle Scholar
  22. 22.
    de Vries LS et al (2004) The spectrum of cranial ultrasound and magnetic resonance imaging abnormalities in congenital cytomegalovirus infection. Neuropediatrics 35(2):113–119PubMedCrossRefGoogle Scholar
  23. 23.
    Trgovcich J et al (1998) Pathogenesis of murine cytomegalovirus infection in neonatal mice. In: Scholz M et al (eds) CMV-related immunopathology monographs in virology. Karger, Basel, SwitzerlandGoogle Scholar
  24. 24.
    Slavuljica I et al (2010) Recombinant mouse cytomegalovirus expressing a ligand for the NKG2D receptor is attenuated and has improved vaccine properties. J Clin Invest 120(12):4532–4545PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Bantug GR et al (2008) CD8+ T lymphocytes control murine cytomegalovirus replication in the central nervous system of newborn animals. J Immunol 181(3):2111–2123PubMedGoogle Scholar
  26. 26.
    Holtappels R et al (2000) Enrichment of immediate-early 1 (m123/pp 89) peptide-specific CD8 T cells in a pulmonary CD62L(lo) memory-effector cell pool during latent murine cytomegalovirus infection of the lungs. J Virol 74(24):11495–11503PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Podlech J et al (2000) Murine model of interstitial cytomegalovirus pneumonia in syngeneic bone marrow transplantation: persistence of protective pulmonary CD8-T-cell infiltrates after clearance of acute infection. J Virol 74(16):7496–7507PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Jonjic S et al (1994) Antibodies are not essential for the resolution of primary cytomegalovirus infection but limit dissemination of recurrent virus. J Exp Med 179(5):1713–1717PubMedCrossRefGoogle Scholar
  29. 29.
    Polic B et al (1998) Hierarchical and redundant lymphocyte subset control precludes cytomegalovirus replication during latent infection. J Exp Med 188(6):1047–1054PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Fowler KB et al (1992) The outcome of congenital cytomegalovirus infection in relation to maternal antibody status. N Engl J Med 326(10):663–667PubMedCrossRefGoogle Scholar
  31. 31.
    Adler SP et al (1995) Immunity induced by primary human cytomegalovirus infection protects against secondary infection among women of childbearing age. J Infect Dis 171(1):26–32PubMedCrossRefGoogle Scholar
  32. 32.
    Ross SA et al (2011) Mixed infection and strain diversity in congenital cytomegalovirus infection. J Infect Dis 204(7):1003–1007PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Boppana SB et al (2001) Intrauterine transmission of cytomegalovirus to infants of women with preconceptional immunity. N Engl J Med 344(18):1366–1371PubMedCrossRefGoogle Scholar
  34. 34.
    Cekinovic D et al (2008) Passive immunization reduces murine cytomegalovirus-induced brain pathology in newborn mice. J Virol 82(24):12172–12180PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Becroft DM (1981) Prenatal cytomegalovirus infection: epidemiology, pathology and pathogenesis. Perspect Pediatr Pathol 6:203–241PubMedGoogle Scholar
  36. 36.
    Wirtz N et al (2008) Polyclonal cytomegalovirus-specific antibodies not only prevent virus dissemination from the portal of entry but also inhibit focal virus spread within target tissues. Med Microbiol Immunol 197(2):151–158PubMedCrossRefGoogle Scholar
  37. 37.
    Harris JP et al (1984) Immunologic and electrophysiological response to cytomegaloviral inner ear infection in the guinea pig. J Infect Dis 150(4):523–530PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Djurdjica Cekinovic
    • 1
  • Vanda Juranic Lisnic
    • 1
  • Stipan Jonjic
    • 2
    Email author
  1. 1.Department for Histology and EmbryologyCenter for Proteomics, School of Medicine, University of RijekaRijekaCroatia
  2. 2.Department for Histology and EmbryologyCenter for Proteomics, School of Medicine, University of RijekaRijekaCroatia

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