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Immunobiology of congenital cytomegalovirus infection of the central nervous system—the murine cytomegalovirus model

Cellular & Molecular Immunology volume 12, pages 180–191 (2015)Cite this article

Abstract

Congenital human cytomegalovirus infection is a leading infectious cause of long-term neurodevelopmental sequelae, including mental retardation and hearing defects. Strict species specificity of cytomegaloviruses has restricted the scope of studies of cytomegalovirus infection in animal models. To investigate the pathogenesis of congenital human cytomegalovirus infection, we developed a mouse cytomegalovirus model that recapitulates the major characteristics of central nervous system infection in human infants, including the route of neuroinvasion and neuropathological findings. Following intraperitoneal inoculation of newborn animals with mouse cytomegalovirus, the virus disseminates to the central nervous system during high-level viremia and replicates in the brain parenchyma, resulting in a focal but widespread, non-necrotizing encephalitis. Central nervous system infection is coupled with the recruitment of resident and peripheral immune cells as well as the expression of a large number of pro-inflammatory cytokines. Although infiltration of cellular constituents of the innate immune response characterizes the early immune response in the central nervous system, resolution of productive infection requires virus-specific CD8+ T cells. Perinatal mouse cytomegalovirus infection results in profoundly altered postnatal development of the mouse central nervous system and long-term motor and sensory disabilities. Based on an enhanced understanding of the pathogenesis of this infection, prospects for novel intervention strategies aimed to improve the outcome of congenital human cytomegalovirus infection are proposed.

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References

  1. Kenneson A, Cannon MJ . Review and meta-analysis of the epidemiology of congenital cytomegalovirus (CMV) infection. Rev Med Virol 2007; 17: 253–276.

    PubMed  Google Scholar 

  2. Wang C, Zhang X, Bialek S, Cannon MJ . Attribution of congenital cytomegalovirus infection to primary versus non-primary maternal infection. Clin Infect Dis 2011; 52: e11–13.

    PubMed  Google Scholar 

  3. Fowler KB, Stagno S, Pass RF . Maternal immunity and prevention of congenital cytomegalovirus infection. JAMA 2003; 289: 1008–1011.

    PubMed  Google Scholar 

  4. Yamamoto AY, Mussi-Pinhata MM, Boppana SB, Novak Z, Wagatsuma VM, Oliveira PeF et al. Human cytomegalovirus reinfection is associated with intrauterine transmission in a highly cytomegalovirus-immune maternal population. Am J Obstet Gynecol 2010; 202: 297.e291–297.298.

    Google Scholar 

  5. Dreher AM, Arora N, Fowler KB, Novak Z, Britt WJ, Boppana SB et al. Spectrum of disease and outcome in children with symptomatic congenital cytomegalovirus infection. J Pediatr 2014; 164: 855–859.

    PubMed  PubMed Central  Google Scholar 

  6. Swanson EC, Schleiss MR . Congenital cytomegalovirus infection: new prospects for prevention and therapy. Pediatr Clin North Am 2013; 60: 335–349.

    PubMed  Google Scholar 

  7. Yamamoto AY, Mussi-Pinhata MM, Isaac MeL, Amaral FR, Carvalheiro CG, Aragon DC et al. Congenital cytomegalovirus infection as a cause of sensorineural hearing loss in a highly immune population. Pediatr Infect Dis J 2011; 30: 1043–1046.

    PubMed  PubMed Central  Google Scholar 

  8. Fowler KB, Boppana SB . Congenital cytomegalovirus (CMV) infection and hearing deficit. J Clin Virol 2006; 35: 226–231.

    PubMed  Google Scholar 

  9. Bristow BN, O'Keefe KA, Shafir SC, Sorvillo FJ . Congenital cytomegalovirus mortality in the United States, 1990–2006. PLoS Negl Trop Dis 2011; 5: e1140.

    PubMed  PubMed Central  Google Scholar 

  10. Boppana SB, Ross SA, Fowler KB . Congenital cytomegalovirus infection: clinical outcome. Clin Infect Dis 2013; 57( Suppl 4): S178–S181.

    PubMed  PubMed Central  Google Scholar 

  11. Mussi-Pinhata MM, Yamamoto AY, Moura Brito RM, de Lima Isaac M, de Carvalho e Oliveira PF, Boppana S et al. Birth prevalence and natural history of congenital cytomegalovirus infection in a highly seroimmune population. Clin Infect Dis 2009; 49: 522–528.

    PubMed  Google Scholar 

  12. Pass RF, Fowler KB, Boppana SB, Britt WJ, Stagno S . Congenital cytomegalovirus infection following first trimester maternal infection: symptoms at birth and outcome. J Clin Virol 2006; 35: 216–220.

    PubMed  Google Scholar 

  13. Anderson KS, Amos CS, Boppana S, Pass R . Ocular abnormalities in congenital cytomegalovirus infection. J Am Optom Assoc 1996; 67: 273–278.

    CAS  PubMed  Google Scholar 

  14. Fowler KB . Congenital cytomegalovirus infection: audiologic outcome. Clin Infect Dis 2013; 57( Suppl 4): S182–S184.

    PubMed  PubMed Central  Google Scholar 

  15. Yamashita Y, Fujimoto C, Nakajima E, Isagai T, Matsuishi T . Possible association between congenital cytomegalovirus infection and autistic disorder. J Autism Dev Disord 2003; 33: 455–459.

    PubMed  Google Scholar 

  16. Sweeten TL, Posey DJ, McDougle CJ . Brief report: autistic disorder in three children with cytomegalovirus infection. J Autism Dev Disord 2004; 34: 583–586.

    PubMed  Google Scholar 

  17. Schleiss MR . Nonprimate models of congenital cytomegalovirus (CMV) infection: gaining insight into pathogenesis and prevention of disease in newborns. ILAR J 2006; 47: 65–72.

    CAS  PubMed  Google Scholar 

  18. Barry PA, Lockridge KM, Salamat S, Tinling SP, Yue Y, Zhou SS et al. Nonhuman primate models of intrauterine cytomegalovirus infection. ILAR J 2006; 47: 49–64.

    CAS  PubMed  Google Scholar 

  19. Reddehase MJ, Podlech J, Grzimek NK . Mouse models of cytomegalovirus latency: overview. J Clin Virol 2002; 25( Suppl 2): S23–S36.

    CAS  PubMed  Google Scholar 

  20. Tarantal AF, Salamat MS, Britt WJ, Luciw PA, Hendrickx AG, Barry PA . Neuropathogenesis induced by rhesus cytomegalovirus in fetal rhesus monkeys (Macaca mulatta). J Infect Dis 1998; 177: 446–450.

    CAS  PubMed  Google Scholar 

  21. Schleiss MR, McVoy MA . Guinea pig cytomegalovirus (GPCMV): a model for the study of the prevention and treatment of maternal–fetal transmission. Future Virol 2010; 5: 207–217.

    PubMed  PubMed Central  Google Scholar 

  22. Britt WJ, Cekinovic D, Jonjic S . Murine model of neonatal cytomegalovirus infection. In: Reddehase MJ (ed.) Cytomegaloviruses: From Molecular Pathogenesis to Intervention. Norfolk: Caister Academic Press, 2013: 119–141.

    Google Scholar 

  23. Tsutsui Y . Developmental disorders of the mouse brain induced by murine cytomegalovirus: animal models for congenital cytomegalovirus infection. Pathol Int 1995; 45: 91–102.

    CAS  PubMed  Google Scholar 

  24. Li RY, Tsutsui Y . Growth retardation and microcephaly induced in mice by placental infection with murine cytomegalovirus. Teratology 2000; 62: 79–85.

    CAS  PubMed  Google Scholar 

  25. Kosugi I, Kawasaki H, Arai Y, Tsutsui Y . Innate immune responses to cytomegalovirus infection in the developing mouse brain and their evasion by virus-infected neurons. Am J Pathol 2002; 161: 919–928.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Shinmura Y, Aiba-Masago S, Kosugi I, Li RY, Baba S, Tsutsui Y . Differential expression of the immediate-early and early antigens in neuronal and glial cells of developing mouse brains infected with murine cytomegalovirus. Am J Pathol 1997; 151: 1331–1340.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Wu CA, Paveglio SA, Lingenheld EG, Zhu L, Lefrançois L, Puddington L . Transmission of murine cytomegalovirus in breast milk: a model of natural infection in neonates. J Virol 2011; 85: 5115–5124.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Koontz T, Bralic M, Tomac J, Pernjak-Pugel E, Bantug G, Jonjic S et al. Altered development of the brain after focal herpesvirus infection of the central nervous system. J Exp Med 2008; 205: 423–435.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Cekinović D, Golemac M, Pugel EP, Tomac J, Cicin-Sain L, Slavuljica I et al. Passive immunization reduces murine cytomegalovirus-induced brain pathology in newborn mice. J Virol 2008; 82: 12172–12180.

    PubMed  PubMed Central  Google Scholar 

  30. Enders G, Daiminger A, Bäder U, Exler S, Enders M . Intrauterine transmission and clinical outcome of 248 pregnancies with primary cytomegalovirus infection in relation to gestational age. J Clin Virol 2011; 52: 244–246.

    PubMed  Google Scholar 

  31. Grassi MP, Clerici F, Perin C, D'Arminio Monforte A, Vago L, Borella M et al. Microglial nodular encephalitis and ventriculoencephalitis due to cytomegalovirus infection in patients with AIDS: two distinct clinical patterns. Clin Infect Dis 1998; 27: 504–508.

    CAS  PubMed  Google Scholar 

  32. Trgovcich J, Stimac D, Polić B, Krmpotić A, Pernjak-Pugel E, Tomac J et al. Immune responses and cytokine induction in the development of severe hepatitis during acute infections with murine cytomegalovirus. Arch Virol 2000; 145: 2601–2618.

    CAS  PubMed  Google Scholar 

  33. Cheeran MC, Lokensgard JR, Schleiss MR . Neuropathogenesis of congenital cytomegalovirus infection: disease mechanisms and prospects for intervention. Clin Microbiol Rev 2009; 22: 99–126, Table of Contents.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Tsutsui Y . Effects of cytomegalovirus infection on embryogenesis and brain development. Congenit Anom (Kyoto) 2009; 49: 47–55.

    CAS  Google Scholar 

  35. Lokensgard JR, Cheeran MC, Gekker G, Hu S, Chao CC, Peterson PK . Human cytomegalovirus replication and modulation of apoptosis in astrocytes. J Hum Virol 1999; 2: 91–101.

    CAS  PubMed  Google Scholar 

  36. McCarthy M, Wood C, Fedoseyeva L, Whittemore SR . Media components influence viral gene expression assays in human fetal astrocyte cultures. J Neurovirol 1995; 1: 275–285.

    CAS  PubMed  Google Scholar 

  37. Cheeran MC, Hu S, Gekker G, Lokensgard JR . Decreased cytomegalovirus expression following proinflammatory cytokine treatment of primary human astrocytes. J Immunol 2000; 164: 926–933.

    CAS  PubMed  Google Scholar 

  38. Cheeran MC, Hu S, Ni HT, Sheng W, Palmquist JM, Peterson PK et al. Neural precursor cell susceptibility to human cytomegalovirus diverges along glial or neuronal differentiation pathways. J Neurosci Res 2005; 82: 839–850.

    CAS  PubMed  Google Scholar 

  39. Fish KN, Soderberg-Naucler C, Mills LK, Stenglein S, Nelson JA . Human cytomegalovirus persistently infects aortic endothelial cells. J Virol 1998; 72: 5661–5668.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Lathey JL, Wiley CA, Verity MA, Nelson JA . Cultured human brain capillary endothelial cells are permissive for infection by human cytomegalovirus. Virology 1990; 176: 266–273.

    CAS  PubMed  Google Scholar 

  41. Poland SD, Costello P, Dekaban GA, Rice GP . Cytomegalovirus in the brain: in vitro infection of human brain-derived cells. J Infect Dis 1990; 162: 1252–1262.

    CAS  PubMed  Google Scholar 

  42. Bentz GL, Jarquin-Pardo M, Chan G, Smith MS, Sinzger C, Yurochko AD . Human cytomegalovirus (HCMV) infection of endothelial cells promotes naive monocyte extravasation and transfer of productive virus to enhance hematogenous dissemination of HCMV. J Virol 2006; 80: 11539–11555.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Abbott NJ, Rönnbäck L, Hansson E . Astrocyte–endothelial interactions at the blood-brain barrier. Nat Rev Neurosci 2006; 7: 41–53.

    CAS  PubMed  Google Scholar 

  44. Wang T, Town T, Alexopoulou L, Anderson JF, Fikrig E, Flavell RA . Toll-like receptor 3 mediates West Nile virus entry into the brain causing lethal encephalitis. Nat Med 2004; 10: 1366–1373.

    CAS  PubMed  Google Scholar 

  45. Spiller OB, Borysiewicz LK, Morgan BP . Development of a model for cytomegalovirus infection of oligodendrocytes. J Gen Virol 1997; 78( Pt 12): 3349–3356.

    CAS  PubMed  Google Scholar 

  46. Odeberg J, Wolmer N, Falci S, Westgren M, Seiger A, Söderberg-Nauclér C . Human cytomegalovirus inhibits neuronal differentiation and induces apoptosis in human neural precursor cells. J Virol 2006; 80: 8929–8939.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Luo MH, Schwartz PH, Fortunato EA . Neonatal neural progenitor cells and their neuronal and glial cell derivatives are fully permissive for human cytomegalovirus infection. J Virol 2008; 82: 9994–10007.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Prösch S, Heine AK, Volk HD, Krüger DH . CCAAT/enhancer-binding proteins alpha and beta negatively influence the capacity of tumor necrosis factor alpha to up-regulate the human cytomegalovirus IE1/2 enhancer/promoter by nuclear factor kappaB during monocyte differentiation. J Biol Chem 2001; 276: 40712–40720.

    PubMed  Google Scholar 

  49. Ossipow V, Descombes P, Schibler U . CCAAT/enhancer-binding protein mRNA is translated into multiple proteins with different transcription activation potentials. Proc Natl Acad Sci USA 1993; 90: 8219–8223.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Wheeler DG, Cooper E . Depolarization strongly induces human cytomegalovirus major immediate-early promoter/enhancer activity in neurons. J Biol Chem 2001; 276: 31978–31985.

    CAS  PubMed  Google Scholar 

  51. Keller MJ, Wu AW, Andrews JI, McGonagill PW, Tibesar EE, Meier JL . Reversal of human cytomegalovirus major immediate-early enhancer/promoter silencing in quiescently infected cells via the cyclic AMP signaling pathway. J Virol 2007; 81: 6669–6681.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Meier JL . Reactivation of the human cytomegalovirus major immediate-early regulatory region and viral replication in embryonal NTera2 cells: role of trichostatin A, retinoic acid, and deletion of the 21-base-pair repeats and modulator. J Virol 2001; 75: 1581–1593.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Odeberg J, Wolmer N, Falci S, Westgren M, Sundtröm E, Seiger A et al. Late human cytomegalovirus (HCMV) proteins inhibit differentiation of human neural precursor cells into astrocytes. J Neurosci Res 2007; 85: 583–593.

    CAS  PubMed  Google Scholar 

  54. Mutnal MB, Cheeran MC, Hu S, Lokensgard JR . Murine cytomegalovirus infection of neural stem cells alters neurogenesis in the developing brain. PLoS ONE 2011; 6: e16211.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. de Vries LS, Gunardi H, Barth PG, Bok LA, Verboon-Maciolek MA, Groenendaal F . The spectrum of cranial ultrasound and magnetic resonance imaging abnormalities in congenital cytomegalovirus infection. Neuropediatrics 2004; 35: 113–119.

    CAS  PubMed  Google Scholar 

  56. Kosmac K, Bantug GR, Pugel EP, Cekinovic D, Jonjic S, Britt WJ . Glucocorticoid treatment of MCMV infected newborn mice attenuates CNS inflammation and limits deficits in cerebellar development. PLoS Pathog 2013; 9: e1003200.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Shinmura Y, Kosugi I, Aiba-Masago S, Baba S, Yong LR, Tsutsui Y . Disordered migration and loss of virus-infected neuronal cells in developing mouse brains infected with murine cytomegalovirus. Acta Neuropathol 1997; 93: 551–557.

    CAS  PubMed  Google Scholar 

  58. Kawasaki H, Tsutsui Y . Brain slice culture for analysis of developmental brain disorders with special reference to congenital cytomegalovirus infection. Congenit Anom (Kyoto) 2003; 43: 105–113.

    CAS  Google Scholar 

  59. Perlman JM, Argyle C . Lethal cytomegalovirus infection in preterm infants: clinical, radiological, and neuropathological findings. Ann Neurol 1992; 31: 64–68.

    CAS  PubMed  Google Scholar 

  60. van Den Pol AN, Mocarski E, Saederup N, Vieira J, Meier TJ . Cytomegalovirus cell tropism, replication, and gene transfer in brain. J Neurosci 1999; 19: 10948–10965.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Marques Dias MJ, Harmant-van Rijckevorsel G, Landrieu P, Lyon G . Prenatal cytomegalovirus disease and cerebral microgyria: evidence for perfusion failure, not disturbance of histogenesis, as the major cause of fetal cytomegalovirus encephalopathy. Neuropediatrics 1984; 15: 18–24.

    CAS  PubMed  Google Scholar 

  62. Kosugi I, Shinmura Y, Kawasaki H, Arai Y, Li RY, Baba S et al. Cytomegalovirus infection of the central nervous system stem cells from mouse embryo: a model for developmental brain disorders induced by cytomegalovirus. Lab Invest 2000; 80: 1373–1383.

    CAS  PubMed  Google Scholar 

  63. McCarthy M, Auger D, Whittemore SR . Human cytomegalovirus causes productive infection and neuronal injury in differentiating fetal human central nervous system neuroepithelial precursor cells. J Hum Virol 2000; 3: 215–228.

    CAS  PubMed  Google Scholar 

  64. Luo MH, Hannemann H, Kulkarni AS, Schwartz PH, O'Dowd JM, Fortunato EA . Human cytomegalovirus infection causes premature and abnormal differentiation of human neural progenitor cells. J Virol 2010; 84: 3528–3541.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Juranic Lisnic V, Babic Cac M, Lisnic B, Trsan T, Mefferd A, Das Mukhopadhyay C et al. Dual analysis of the murine cytomegalovirus and host cell transcriptomes reveal new aspects of the virus–host cell interface. PLoS Pathog 2013; 9: e1003611.

    PubMed  PubMed Central  Google Scholar 

  66. Cheng Y, Sudarov A, Szulc KU, Sgaier SK, Stephen D, Turnbull DH et al. The Engrailed homeobox genes determine the different foliation patterns in the vermis and hemispheres of the mammalian cerebellum. Development 2010; 137: 519–529.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Orvis GD, Hartzell AL, Smith JB, Barraza LH, Wilson SL, Szulc KU et al. The engrailed homeobox genes are required in multiple cell lineages to coordinate sequential formation of fissures and growth of the cerebellum. Dev Biol 2012; 367: 25–39.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Luján R, Shigemoto R, López-Bendito G . Glutamate and GABA receptor signalling in the developing brain. Neuroscience 2005; 130: 567–580.

    PubMed  Google Scholar 

  69. van den Pol AN, Robek MD, Ghosh PK, Ozduman K, Bandi P, Whim MD et al. Cytomegalovirus induces interferon-stimulated gene expression and is attenuated by interferon in the developing brain. J Virol 2007; 81: 332–348.

    CAS  PubMed  Google Scholar 

  70. Jordan I, Lipkin WI . Borna disease virus. Rev Med Virol 2001; 11: 37–57.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Peterson KE, Robertson SJ, Portis JL, Chesebro B . Differences in cytokine and chemokine responses during neurological disease induced by polytropic murine retroviruses map to separate regions of the viral envelope gene. J Virol 2001; 75: 2848–2856.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Peterson KE, Errett JS, Wei T, Dimcheff DE, Ransohoff R, Kuziel WA et al. MCP-1 and CCR2 contribute to non-lymphocyte-mediated brain disease induced by Fr98 polytropic retrovirus infection in mice: role for astrocytes in retroviral neuropathogenesis. J Virol 2004; 78: 6449–6458.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Portis JL, Czub S, Robertson S, McAtee F, Chesebro B . Characterization of a neurologic disease induced by a polytropic murine retrovirus: evidence for differential targeting of ecotropic and polytropic viruses in the brain. J Virol 1995; 69: 8070–8075.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Bantug GR, Cekinovic D, Bradford R, Koontz T, Jonjic S, Britt WJ . CD8+ T lymphocytes control murine cytomegalovirus replication in the central nervous system of newborn animals. J Immunol 2008; 181: 2111–2123.

    CAS  PubMed  Google Scholar 

  75. Lokensgard JR, Cheeran MC, Hu S, Gekker G, Peterson PK . Glial cell responses to herpesvirus infections: role in defense and immunopathogenesis. J Infect Dis 2002; 186( Suppl 2): S171–S179.

    PubMed  Google Scholar 

  76. Cheeran MC, Hu S, Yager SL, Gekker G, Peterson PK, Lokensgard JR . Cytomegalovirus induces cytokine and chemokine production differentially in microglia and astrocytes: antiviral implications. J Neurovirol 2001; 7: 135–147.

    CAS  PubMed  Google Scholar 

  77. Cheeran MC, Hu S, Sheng WS, Peterson PK, Lokensgard JR . CXCL10 production from cytomegalovirus-stimulated microglia is regulated by both human and viral interleukin-10. J Virol 2003; 77: 4502–4515.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Cheeran MC, Gekker G, Hu S, Min X, Cox D, Lokensgard JR . Intracerebral infection with murine cytomegalovirus induces CXCL10 and is restricted by adoptive transfer of splenocytes. J Neurovirol 2004; 10: 152–162.

    CAS  PubMed  Google Scholar 

  79. Cheeran MC, Gekker G, Hu S, Palmquist JM, Lokensgard JR . T cell-mediated restriction of intracerebral murine cytomegalovirus infection displays dependence upon perforin but not interferon-gamma. J Neurovirol 2005; 11: 274–280.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Cheeran MC, Hu S, Palmquist JM, Bakken T, Gekker G, Lokensgard JR . Dysregulated interferon-gamma responses during lethal cytomegalovirus brain infection of IL-10-deficient mice. Virus Res 2007; 130: 96–102.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Kotenko SV, Saccani S, Izotova LS, Mirochnitchenko OV, Pestka S . Human cytomegalovirus harbors its own unique IL-10 homolog (cmvIL-10). Proc Natl Acad Sci USA 2000; 97: 1695–1700.

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Mutnal MB, Hu S, Little MR, Lokensgard JR . Memory T cells persisting in the brain following MCMV infection induce long-term microglial activation via interferon-γ. J Neurovirol 2011; 17: 424–437.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Mocarski ES . Immunomodulation by cytomegaloviruses: manipulative strategies beyond evasion. Trends Microbiol 2002; 10: 332–339.

    CAS  PubMed  Google Scholar 

  84. Andrews DM, Matthews VB, Sammels LM, Carrello AC, McMinn PC . The severity of murray valley encephalitis in mice is linked to neutrophil infiltration and inducible nitric oxide synthase activity in the central nervous system. J Virol 1999; 73: 8781–8790.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Mutnal MB, Cheeran MC, Hu S, Little MR, Lokensgard JR . Excess neutrophil infiltration during cytomegalovirus brain infection of interleukin-10-deficient mice. J Neuroimmunol 2010; 227: 101–110.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Daniels KA, Devora G, Lai WC, O'Donnell CL, Bennett M, Welsh RM . Murine cytomegalovirus is regulated by a discrete subset of natural killer cells reactive with monoclonal antibody to Ly49H. J Exp Med 2001; 194: 29–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Welsh RM, Brubaker JO, Vargas-Cortes M, O'Donnell CL . Natural killer (NK) cell response to virus infections in mice with severe combined immunodeficiency. The stimulation of NK cells and the NK cell-dependent control of virus infections occur independently of T and B cell function. J Exp Med 1991; 173: 1053–1063.

    CAS  PubMed  Google Scholar 

  88. Krmpotic A, Bubic I, Polic B, Lucin P, Jonjic S . Pathogenesis of murine cytomegalovirus infection. Microbes Infect 2003; 5: 1263–1277.

    CAS  PubMed  Google Scholar 

  89. Wakim LM, Woodward-Davis A, Bevan MJ . Memory T cells persisting within the brain after local infection show functional adaptations to their tissue of residence. Proc Natl Acad Sci USA 2010; 107: 17872–17879.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Munks MW, Cho KS, Pinto AK, Sierro S, Klenerman P, Hill AB . Four distinct patterns of memory CD8 T cell responses to chronic murine cytomegalovirus infection. J Immunol 2006; 177: 450–458.

    CAS  PubMed  Google Scholar 

  91. Holtappels R, Simon CO, Munks MW, Thomas D, Deegen P, Kühnapfel B et al. Subdominant CD8 T-cell epitopes account for protection against cytomegalovirus independent of immunodomination. J Virol 2008; 82: 5781–5796.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Sylwester AW, Mitchell BL, Edgar JB, Taormina C, Pelte C, Ruchti F et al. Broadly targeted human cytomegalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjects. J Exp Med 2005; 202: 673–685.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Harty JT, Tvinnereim AR, White DW . CD8+ T cell effector mechanisms in resistance to infection. Annu Rev Immunol 2000; 18: 275–308.

    CAS  PubMed  Google Scholar 

  94. Koszinowski UH, Reddehase MJ, Jonjic S . The role of CD4 and CD8 T cells in viral infections. Curr Opin Immunol 1991; 3: 471–475.

    CAS  PubMed  Google Scholar 

  95. Zhou S, Ou R, Huang L, Price GE, Moskophidis D . Differential tissue-specific regulation of antiviral CD8+ T-cell immune responses during chronic viral infection. J Virol 2004; 78: 3578–3600.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Shrestha B, Samuel MA, Diamond MS . CD8+ T cells require perforin to clear West Nile virus from infected neurons. J Virol 2006; 80: 119–129.

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Griffin DE . Immune responses to RNA-virus infections of the CNS. Nat Rev Immunol 2003; 3: 493–502.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Binder GK, Griffin DE . Interferon-gamma-mediated site-specific clearance of alphavirus from CNS neurons. Science 2001; 293: 303–306.

    CAS  PubMed  Google Scholar 

  99. Patterson CE, Daley JK, Rall GF . Neuronal survival strategies in the face of RNA viral infection. J Infect Dis 2002; 186( Suppl 2): S215–S219.

    PubMed  Google Scholar 

  100. Jonjić S, Pavić I, Lucin P, Rukavina D, Koszinowski UH . Efficacious control of cytomegalovirus infection after long-term depletion of CD8+ T lymphocytes. J Virol 1990; 64: 5457–5464.

    PubMed  PubMed Central  Google Scholar 

  101. Reddehase MJ, Weiland F, Münch K, Jonjic S, Lüske A, Koszinowski UH . Interstitial murine cytomegalovirus pneumonia after irradiation: characterization of cells that limit viral replication during established infection of the lungs. J Virol 1985; 55: 264–273.

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Reddehase MJ, Mutter W, Münch K, Bühring HJ, Koszinowski UH . CD8-positive T lymphocytes specific for murine cytomegalovirus immediate-early antigens mediate protective immunity. J Virol 1987; 61: 3102–3108.

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Humphreys IR, de Trez C, Kinkade A, Benedict CA, Croft M, Ware CF . Cytomegalovirus exploits IL-10-mediated immune regulation in the salivary glands. J Exp Med 2007; 204: 1217–1225.

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Cavanaugh VJ, Deng Y, Birkenbach MP, Slater JS, Campbell AE . Vigorous innate and virus-specific cytotoxic T-lymphocyte responses to murine cytomegalovirus in the submaxillary salivary gland. J Virol 2003; 77: 1703–1717.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Walton SM, Mandaric S, Torti N, Zimmermann A, Hengel H, Oxenius A . Absence of cross-presenting cells in the salivary gland and viral immune evasion confine cytomegalovirus immune control to effector CD4 T cells. PLoS Pathog 2011; 7: e1002214.

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Graham JB, da Costa A, Lund JM . Regulatory T cells shape the resident memory T cell response to virus infection in the tissues. J Immunol 2014; 192: 683–690.

    CAS  PubMed  Google Scholar 

  107. Tishon A, Lewicki H, Andaya A, McGavern D, Martin L, Oldstone MB . CD4 T cell control primary measles virus infection of the CNS: regulation is dependent on combined activity with either CD8 T cells or with B cells: CD4, CD8 or B cells alone are ineffective. Virology 2006; 347: 234–245.

    CAS  PubMed  Google Scholar 

  108. Griffin D, Levine B, Tyor W, Ubol S, Desprès P . The role of antibody in recovery from alphavirus encephalitis. Immunol Rev 1997; 159: 155–161.

    CAS  PubMed  Google Scholar 

  109. Hooper DC, Phares TW, Fabis MJ, Roy A . The production of antibody by invading B cells is required for the clearance of rabies virus from the central nervous system. PLoS Negl Trop Dis 2009; 3: e535.

    PubMed  PubMed Central  Google Scholar 

  110. Fragkoudis R, Ballany CM, Boyd A, Fazakerley JK . In Semliki Forest virus encephalitis, antibody rapidly clears infectious virus and is required to eliminate viral material from the brain, but is not required to generate lesions of demyelination. J Gen Virol 2008; 89: 2565–2568.

    CAS  PubMed  Google Scholar 

  111. Mutnal MB, Hu S, Lokensgard JR . Persistent humoral immune responses in the CNS limit recovery of reactivated murine cytomegalovirus. PLoS ONE 2012; 7: e33143.

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Jonjić S, Pavić I, Polić B, Crnković I, Lucin P, Koszinowski UH . Antibodies are not essential for the resolution of primary cytomegalovirus infection but limit dissemination of recurrent virus. J Exp Med 1994; 179: 1713–1717.

    PubMed  Google Scholar 

  113. Polić B, Hengel H, Krmpotić A, Trgovcich J, Pavić I, Luccaronin P et al. Hierarchical and redundant lymphocyte subset control precludes cytomegalovirus replication during latent infection. J Exp Med 1998; 188: 1047–1054.

    PubMed  PubMed Central  Google Scholar 

  114. Nigro G, Adler SP, La Torre R, Best AM ; Congenital Cytomegalovirus Collaborating Group. Passive immunization during pregnancy for congenital cytomegalovirus infection. N Engl J Med 2005; 353: 1350–1362.

    CAS  PubMed  Google Scholar 

  115. Nigro G, Adler SP, Parruti G, Anceschi MM, Coclite E, Pezone I et al. Immunoglobulin therapy of fetal cytomegalovirus infection occurring in the first half of pregnancy—a case–control study of the outcome in children. J Infect Dis 2012; 205: 215–227.

    CAS  PubMed  Google Scholar 

  116. Buxmann H, Stackelberg OM, Schlößer RL, Enders G, Gonser M, Meyer-Wittkopf M et al. Use of cytomegalovirus hyperimmunoglobulin for prevention of congenital cytomegalovirus disease: a retrospective analysis. J Perinat Med 2012; 40: 439–446.

    PubMed  Google Scholar 

  117. Visentin S, Manara R, Milanese L, da Roit A, Forner G, Salviato E et al. Early primary cytomegalovirus infection in pregnancy: maternal hyperimmunoglobulin therapy improves outcomes among infants at 1 year of age. Clin Infect Dis 2012; 55: 497–503.

    CAS  PubMed  Google Scholar 

  118. Adler SP . Immunoprophylaxis against cytomegalovirus disease. Scand J Infect Dis Suppl 1995; 99: 105–109.

    CAS  PubMed  Google Scholar 

  119. Fowler KB, Stagno S, Pass RF, Britt WJ, Boll TJ, Alford CA . The outcome of congenital cytomegalovirus infection in relation to maternal antibody status. N Engl J Med 1992; 326: 663–667.

    CAS  PubMed  Google Scholar 

  120. Nigro G, Capretti I, Manganello AM, Best AM, Adler SP . Primary maternal cytomegalovirus infections during pregnancy: association of CMV hyperimmune globulin with gestational age at birth and birth weight. J Matern Fetal Neonatal Med 2014.

  121. Boppana SB, Britt WJ . Synopsis of Clinical Aspects of human cytomegalovirus disease. In: Reddehase MJ (ed.) Cytomegaloviruses: From Molecular Pathogenesis to Intervention. Norfolk: Caister Academic Press, 2013: 1–25.

    Google Scholar 

  122. Revello MG, Lazzarotto T, Guerra B, Spinillo A, Ferrazzi E, Kustermann A et al. A randomized trial of hyperimmune globulin to prevent congenital cytomegalovirus. N Engl J Med 2014; 370: 1316–1326.

    CAS  PubMed  Google Scholar 

  123. Auerbach MR, Yan D, Vij R, Hongo JA, Nakamura G, Vernes JM et al. A Neutralizing anti-gH/gL monoclonal antibody is protective in the guinea pig model of congenital CMV infection. PLoS Pathog 2014; 10: e1004060.

    PubMed  PubMed Central  Google Scholar 

  124. Fouts AE, Chan P, Stephan JP, Vandlen R, Feierbach B . Antibodies against the gH/gL/UL128/UL130/UL131 complex comprise the majority of the anti-cytomegalovirus (anti-CMV) neutralizing antibody response in CMV hyperimmune globulin. J Virol 2012; 86: 7444–7447.

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Boppana SB, Rivera LB, Fowler KB, Mach M, Britt WJ . Intrauterine transmission of cytomegalovirus to infants of women with preconceptional immunity. N Engl J Med 2001; 344: 1366–1371.

    CAS  PubMed  Google Scholar 

  126. Ross SA, Novak Z, Pati S, Boppana SB . Overview of the diagnosis of cytomegalovirus infection. Infect Disord Drug Targets 2011; 11: 466–474.

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Maidji E, McDonagh S, Genbacev O, Tabata T, Pereira L . Maternal antibodies enhance or prevent cytomegalovirus infection in the placenta by neonatal Fc receptor-mediated transcytosis. Am J Pathol 2006; 168: 1210–1226.

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Slavuljica I, Busche A, Babic M, Mitrovic M, Gasparovic I, Cekinovic D et al. Recombinant mouse cytomegalovirus expressing a ligand for the NKG2D receptor is attenuated and has improved vaccine properties. J Clin Invest 2010; 120: 4532–4545.

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Boppana SB, Britt WJ . Cytomegalovirus. In: Newton VE (ed.) Infection and Hearing Impairment. London: Whurr Publishers Ltd, 2006: 67–92.

    Google Scholar 

  130. Davis GL . In vitro models of viral-induced congenital deafness. Am J Otol 1981; 3: 156–160.

    CAS  PubMed  Google Scholar 

  131. Rarey KE, Davis LE . Temporal bone histopathology 14 years after cytomegalic inclusion disease: a case study. Laryngoscope 1993; 103: 904–909.

    CAS  PubMed  Google Scholar 

  132. Strauss M . A clinical pathologic study of hearing loss in congenital cytomegalovirus infection. Laryngoscope 1985; 95: 951–962.

    CAS  PubMed  Google Scholar 

  133. Gabrielli L, Bonasoni MP, Santini D, Piccirilli G, Chiereghin A, Guerra B et al. Human fetal inner ear involvement in congenital cytomegalovirus infection. Acta Neuropathol Commun 2013; 1: 63.

    PubMed  PubMed Central  Google Scholar 

  134. Teissier N, Delezoide AL, Mas AE, Khung-Savatovsky S, Bessières B, Nardelli J et al. Inner ear lesions in congenital cytomegalovirus infection of human fetuses. Acta Neuropathol 2011; 122: 763–774.

    PubMed  Google Scholar 

  135. Ciuman RR . Auditory and vestibular hair cell stereocilia: relationship between functionality and inner ear disease. J Laryngol Otol 2011; 125: 991–1003.

    CAS  PubMed  Google Scholar 

  136. Strauss M . Human cytomegalovirus labyrinthitis. Am J Otolaryngol 1990; 11: 292–298.

    CAS  PubMed  Google Scholar 

  137. Zagólski O . Vestibular-evoked myogenic potentials and caloric stimulation in infants with congenital cytomegalovirus infection. J Laryngol Otol 2008; 122: 574–579.

    PubMed  Google Scholar 

  138. Li L, Kosugi I, Han GP, Kawasaki H, Arai Y, Takeshita T et al. Induction of cytomegalovirus-infected labyrinthitis in newborn mice by lipopolysaccharide: a model for hearing loss in congenital CMV infection. Lab Invest 2008; 88: 722–730.

    CAS  PubMed  Google Scholar 

  139. Schachtele SJ, Mutnal MB, Schleiss MR, Lokensgard JR . Cytomegalovirus-induced sensorineural hearing loss with persistent cochlear inflammation in neonatal mice. J Neurovirol 2011; 17: 201–211.

    PubMed  PubMed Central  Google Scholar 

  140. Schraff SA, Brown DK, Schleiss MR, Meinzen-Derr J, Greinwald JH, Choo DI . The role of CMV inflammatory genes in hearing loss. Otol Neurotol 2007; 28: 964–969.

    PubMed  Google Scholar 

  141. Juanjuan C, Yan F, Li C, Haizhi L, Ling W, Xinrong W et al. Murine model for congenital CMV infection and hearing impairment. Virol J 2011; 8: 70.

    PubMed  PubMed Central  Google Scholar 

  142. Ahmed A . Antiviral treatment of cytomegalovirus infection. Infect Disord Drug Targets 2011; 11: 475–503.

    CAS  PubMed  Google Scholar 

  143. Kimberlin DW, Lin CY, Sánchez PJ, Demmler GJ, Dankner W, Shelton M et al. Effect of ganciclovir therapy on hearing in symptomatic congenital cytomegalovirus disease involving the central nervous system: a randomized, controlled trial. J Pediatr 2003; 143: 16–25.

    CAS  PubMed  Google Scholar 

  144. Oliver SE, Cloud GA, Sánchez PJ, Demmler GJ, Dankner W, Shelton M et al. Neurodevelopmental outcomes following ganciclovir therapy in symptomatic congenital cytomegalovirus infections involving the central nervous system. J Clin Virol 2009; 46( Suppl 4): S22–S26.

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Coll O, Benoist G, Ville Y, Weisman LE, Botet F, Anceschi MM et al. Guidelines on CMV congenital infection. J Perinat Med 2009; 37: 433–445.

    PubMed  Google Scholar 

  146. Kotton CN, Kumar D, Caliendo AM, Asberg A, Chou S, Danziger-Isakov L et al. Updated international consensus guidelines on the management of cytomegalovirus in solid-organ transplantation. Transplantation 2013; 96: 333–360.

    CAS  PubMed  Google Scholar 

  147. Interim analysis of the Cytotec Phase III trial in congenial cytomegalovirus (CMV) infection shows clear indication of efficacy. Dreieic: Biotest AG. Available from: http://www.biotest.de/ww/en/pub/investor_relations/news/newsdetails.cfm?newsID=1025191. Accessed date 31.5.2014.

  148. Clinicaltrials.gov. Efficacy study of human cytomegalovirus (HCMV) hyperimmune globulin to prevent congenital HCMV infection (CHIP). Bethesda, MD: US NIH. Available from: http://clinicaltrials.gov/ct2/show/record/NCT00881517. Accessed date 31.5.2014.

  149. Arvin AM, Fast P, Myers M, Plotkin S, Rabinovich R . National Vaccine Advisory Committee. Vaccine development to prevent cytomegalovirus disease: report from the National Vaccine Advisory Committee. Clin Infect Dis 2004; 39: 233–239.

    PubMed  Google Scholar 

  150. Wang D, Fu TM . Progress on human cytomegalovirus vaccines for prevention of congenital infection and disease. Curr Opin Virol 2014; 6C: 13–23.

    Google Scholar 

  151. Dasari V, Smith C, Khanna R . Recent advances in designing an effective vaccine to prevent cytomegalovirus-associated clinical diseases. Expert Rev Vaccines 2013; 12: 661–676.

    CAS  PubMed  Google Scholar 

  152. Pass RF, Zhang C, Evans A, Simpson T, Andrews W, Huang ML et al. Vaccine prevention of maternal cytomegalovirus infection. N Engl J Med 2009; 360: 1191–1199.

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Griffiths PD, McLean A, Emery VC . Encouraging prospects for immunisation against primary cytomegalovirus infection. Vaccine 2001; 19: 1356–1362.

    CAS  PubMed  Google Scholar 

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Acknowledgements

S Jonjić is supported by NIH grant 1RO1AI083201-01, and W J Britt is supported by NIH grants 1RO1AI089956-01A1 and 1R01NS065845-01.

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Authors and Affiliations

  1. Department of Histology and Embryology, School of Medicine, University of Rijeka, Rijeka, Croatia

    Irena Slavuljica, Daria Kveštak, Peter Csaba Huszthy & Stipan Jonjić

  2. Department of Infectious Diseases, School of Medicine, University of Rijeka, Rijeka, Croatia

    Irena Slavuljica

  3. Department of Immunology, Institute of Clinical Medicine, University of Oslo, Oslo, Norway

    Peter Csaba Huszthy

  4. Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL, USA

    Kate Kosmac & William J Britt

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  1. Irena Slavuljica
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Correspondence to Stipan Jonjić.

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Slavuljica, I., Kveštak, D., Csaba Huszthy, P. et al. Immunobiology of congenital cytomegalovirus infection of the central nervous system—the murine cytomegalovirus model. Cell Mol Immunol 12, 180–191 (2015). https://doi.org/10.1038/cmi.2014.51

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