Altered development of the brain after focal herpesvirus infection of the central nervous system

Koontz, Thad; Bralić, Marina; Tomac, Jelena; Pugel, Ester Pernjak; Bantug, Glen; Jonjić, Stipan; Britt, William J.

doi:10.1084/jem.20071489

Cited by 76 publications

(195 citation statements)

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“…The hallmark of CNS infection is focal involvement in different regions of the brain that is consistent with hematogenous virus spread and is nearly indistinguishable from histological findings in infants with congenital HCMV infection. 28 Discrete foci containing small numbers of MCMV-infected cells are distributed throughout the cerebrum, including the cortex, hippocampus, periventricular region as well as cerebellum and meninges overlaying different regions of the brain with a variety of resident cells being infected 28 (Figure 1b). Mononuclear cell infiltrates, mainly composed of T cells and F4/80 1 macrophages/microglia, surround the foci of infection (Figure 1b).…”

Section: Shows No Cell Tropism In the Cnsmentioning

confidence: 99%

“…Virus titers peak in the CNS between postnatal days 10 and 14, and infectious virus becomes undetectable by day 21. 28,29 After the resolution of productive infection, clearance of the viral genome is not achieved, and MCMV establishes lifelong latent infection with potential periodic reactivations. The hallmark of CNS infection is focal involvement in different regions of the brain that is consistent with hematogenous virus spread and is nearly indistinguishable from histological findings in infants with congenital HCMV infection.…”

Section: Shows No Cell Tropism In the Cnsmentioning

confidence: 99%

“…MCMV infection of newborn mice, the virus disseminates to the CNS during hematogenous spread and replicates in the brain parenchyma. 28,29 The latter model, when compared to models that utilize direct intracranial inoculation of the virus, more closely recapitulates the presumed route of HCMV dissemination into the CNS during systemic viremia. However, the exact mechanism that the virus utilizes to cross the blood-brain barrier is unknown.…”

mentioning

confidence: 99%

“…29 CSN infection of newborn mice consistently results in widespread, focal, non-necrotizing encephalitis and defects in brain development. 28 It should be stated that the neonatal mouse CNS is embryologically equivalent to the human fetus at 15 weeks of gestation and that HCMV infection in humans is most frequently acquired during the early periods of the second trimester of pregnancy; 30 therefore, CNS disease in newborn mice closely mimics that associated with vertically transmitted HCMV infection in humans. 22 Finally, mice infected with MCMV during the neonatal period exhibit neurobehavioral sequelae, such as impaired performance on a stationary balance beam and sensorineural hearing loss, as adult animals (Britt WJ, 2014, unpubl.…”

mentioning

confidence: 99%

“…inoculation of the virus. 28 Following i.p. MCMV infection of newborn mice, the virus disseminates to the CNS during hematogenous spread and replicates in the brain parenchyma.…”

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confidence: 99%

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

et al. 2014

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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 1 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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Section: Shows No Cell Tropism In the Cnsmentioning

confidence: 99%

Section: Shows No Cell Tropism In the Cnsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

“…inoculation of the virus. 28 Following i.p. MCMV infection of newborn mice, the virus disseminates to the CNS during hematogenous spread and replicates in the brain parenchyma.…”

mentioning

confidence: 99%

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

et al. 2014

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Aberrant fetal macrophage/microglial reactions to cytomegalovirus infection

Sakao-Suzuki

Kawasaki

Akamatsu

et al. 2014

Ann Clin Transl Neurol

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ObjectiveCongenital cytomegalovirus (CMV) infection is the leading viral cause of neurodevelopmental disorders in humans, with the most severe and permanent sequelae being those affecting the cerebrum. As the fetal immune reactions to congenital CMV infection in the brain and their effects on cerebral development remain elusive, our aim was to investigate primitive innate immunity to CMV infection and its effects on cerebral corticogenesis in a mouse model for congenital CMV infection using a precise intraplacental inoculation method.MethodsAt 13.5 embryonic days (E13.5), pregnant C57BL/6 mice were intraplacentally infected with murine CMV (MCMV). Placentas and fetal organs were collected at 1, 3, and 5 days postinfection and analyzed.ResultsMCMV antigens were found frequently in perivascular macrophages, and subsequently in neural stem/progenitor cells (NSPCs). With increased expression of inducible nitric oxide synthase and proinflammatory cytokines, activated macrophages infiltrated into the infectious foci. In addition to the infected area, the numbers of both meningeal macrophages and parenchymal microglia increased even in the uninfected areas of MCMV-infected brain due to recruitment of their precursors from other sites. A bromodeoxyuridine (BrdU) incorporation experiment demonstrated that MCMV infection globally disrupted the self-renewal of NSPCs. Furthermore, BrdU-labeled neurons, particularly Brn2+ neurons of upper layers II/III in the cortical plate, decreased in number significantly in the MCMV-infected E18.5 cerebrum.InterpretationBrain macrophages are crucial for innate immunity during MCMV infection in the fetal brain, while their aberrant recruitment and activation may adversely impact on the stemness of NSPCs, resulting in neurodevelopmental disorders.

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Cytomegalovirus Infection: Mouse Model

et al. 2018

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This unit describes procedures for infecting newborn and adult mice with murine cytomegalovirus (MCMV). Methods are included for propagating MCMV in cell cultures and for preparing a more virulent form of MCMV from salivary glands of infected mice. A plaque assay is provided for determining MCMV titers of infected tissues or virus stocks. Also, a method is described for preparing the murine embryonic fibroblasts used for propagating MCMV and for the plaque assay. © 2018 by John Wiley & Sons, Inc.

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Altered development of the brain after focal herpesvirus infection of the central nervous system

Cited by 76 publications

References 74 publications

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

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

Aberrant fetal macrophage/microglial reactions to cytomegalovirus infection

Cytomegalovirus Infection: Mouse Model

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