Cytomegalovirus Infection of the Central Nervous System Stem Cells from Mouse Embryo: A Model for Developmental Brain Disorders Induced by Cytomegalovirus

Kosugi, Isao; Shinmura, Yuichiro; Kawasaki, Hideya; Arai, Yoshifumi; Li, Ren-Yong; Baba, Satoshi; Tsutsui, Yoshihiro

doi:10.1038/labinvest.3780145

Cited by 73 publications

(97 citation statements)

References 43 publications

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“…Studies of human CMV, a ␤-herpesvirus that is 67% homologous to HHV-6 at the protein level (Dominguez et al, 1999), as well as murine CMV have demonstrated an inhibition of the G 1 /S phase transition in several distinct cell systems (Wiebusch and Hagemeier, 1999;Kosugi et al, 2000;Flemington, 2001;Castillo and Kowalik, 2002). HHV-6 has been demonstrated to be able to infect and arrest human bone marrow progenitor cells in vitro (Luppi et al, 1999;Isomura et al, 2003) and in vivo (Wilborn et al, 1994;Rosenfeld et al, 1995;Secchiero et al, 1995) and to suppress proliferative responses to antigens and mitogens (Burd and Carrigan, 1993;Horvat et al, 1993;Carrigan and Knox, 1995).…”

Section: Discussionmentioning

confidence: 99%

Infection with an Endemic Human Herpesvirus Disrupts Critical Glial Precursor Cell Properties

Dietrich¹,

Blumberg²,

Roshal³

et al. 2004

J. Neurosci.

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Human herpesvirus 6 (HHV-6), a common resident virus of the human CNS, has been implicated in both acute and chronic inflammatory-demyelinating diseases. Although HHV-6 persists within the human CNS and has been described to infect mature oligodendrocytes, nothing is known about the susceptibility of glial precursors, the ancestors of myelin-producing oligodendrocytes, to viral infection.We show that HHV-6 infects human glial precursor cells in vitro. Active infection was demonstrated by both electron microscopy and expression of viral gene transcripts and proteins, with subsequent formation of cell syncytia. Infection leads to alterations in cell morphology and impairment of cell replication but not increased cell death. Infected cells showed decreased proliferation as measured by bromodeoxyuridine uptake, which was confirmed by blunting of the cell growth rate of infected cells compared with uninfected controls over time. The detailed analysis using novel, fluorescent-labeled HHV-6A or HHV-6B reagents demonstrated strong G 1 /S phase inhibition in infected precursor cells. Cell cycle arrest in HHV-6-infected cells was associated with a profound decrease in the expression of the glial progenitor cell marker A2B5 and a corresponding increase in the oligodendrocyte differentiation marker GalC.These data demonstrate for the first time that infection of primary human glial precursor cells with a neurologically relevant human herpesvirus causes profound alterations of critical precursor cell properties. In light of recent observations that repair of CNS demyelination is dependent on the generation of mature oligodendrocytes from the glial precursor cell pool, these findings may have broad implications for both the ineffective repair seen in demyelinating diseases and the disruption of normal glial maturation.

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Section: Discussionmentioning

confidence: 99%

Infection with an Endemic Human Herpesvirus Disrupts Critical Glial Precursor Cell Properties

Dietrich¹,

Blumberg²,

Roshal³

et al. 2004

J. Neurosci.

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“…38,46,47,53,63 CMV infection causes NSPCs to alter their differentiation program, and it inhibits the proliferation and induces the apoptosis of NSPCs. 47,62,64 Whole-genome expression analysis found rapid downregulation of the mRNA levels of several genes important for maintaining NSPC multipotency and for establishing their neural identity (nestin, doublecortin, sex-determining home box 2 and glial fibrillary acidic protein). 64 It is thus possible that HCMV infection causes in utero CNS defects by inducing both premature and abnormal differentiation of NSPCs.…”

Section: Cmv-induced Developmental Brain Abnormalitiesmentioning

confidence: 99%

“…CNS structural abnormalities and functional disorders caused by congenital CMV infection may be due to MCMV infection of radial glial cells, which play an important role in guiding neuron migration in the neonatal mouse cerebrum, [58][59][60] but could also be the result of an insufficient cerebral blood supply caused by endothelial cell infection and inflammation of the vessel wall 61 (Figure 1b) or by infection of NSPCs. 47,54,62 NSPCs, which are located predominantly in the ventricular/periventricular zone, have the ability to migrate, proliferate, and differentiate into neurons, astrocytes, and oligodendrocytes and are fully permissive to CMV infection. 38,46,47,53,63 CMV infection causes NSPCs to alter their differentiation program, and it inhibits the proliferation and induces the apoptosis of NSPCs.…”

Section: Cmv-induced Developmental Brain Abnormalitiesmentioning

confidence: 99%

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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“…Data are expressed as the mean Ϯ SD of at least three independent experiments. ૽ p Ͻ 0.05 and ૽૽ p Ͻ 0.01. walls, including the ventricular zone and SVZ (Becroft, 1981;Kosugi et al, 2000;Li and Tsutsui, 2000;Perlman and Argyle, 1992;Shinmura et al, 1997aShinmura et al, , 1997bvan den Pol et al, 2000).In isolated cell cultures infected with MCMV, the kinetics of viral titers and viral antigen expression of neural stem cells were slower than those of mouse embryonic fibroblasts, which are known to be fully permissive for MCMV replication (Kosugi et al, 2000). Similarly, the rate of viral replication in glial cultures was significantly higher than that in neuronal cultures (van den Pol et al, 1999).…”

mentioning

confidence: 99%

The Amount of Immature Glial Cells in Organotypic Brain Slices Determines the Susceptibility to Murine Cytomegalovirus Infection

Kawasaki

Kosugi

Arai

et al. 2002

Laboratory Investigation

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SUMMARY: Cytomegalovirus (CMV) is the most common infectious cause of congenital anomalies of the brain and also causes brain damage in immunocompromised individuals. We investigated the effects of murine cytomegalovirus (MCMV) infection on the developing mouse brain in terms of susceptible cells and age-related resistance to MCMV in brain slice cultures. Brain slices from BALB/c mice at different developmental stages were infected with recombinant MCMV in which the lacZ gene was inserted into a late gene. The subventricular zone and cortical marginal region were the sites most susceptible to MCMV infection, and the susceptibility declined with the development of the brain. Immunohistochemical staining showed that the virus-susceptible cells were positive for GFAP, nestin, and Musashi-1, and that most of the infected cells were positive for the proliferative cell nuclear antigen and labeled with bromodeoxyuridine. These results suggest that the susceptible cells in the subventricular zone are immature glial cells, including neural progenitor cells. Immature glial cells proliferated when the brain slices were cultured for a prolonged time and furthermore, they showed themselves to be susceptible to virus infection even under serum-free conditions. These results suggest that the amount of immature glial cells, which include neural progenitor cells, in the developing brain or in the damaged brain with neural proliferation may be closely associated with the susceptibility of the brain to CMV infection in humans. (Lab Invest 2002, 82:1347-1358. C ytomegalovirus (CMV) is the most significant infectious cause of congenital anomalies of the central nervous system (CNS) caused by intrauterine infection in humans (Ho, 1991;Weller, 1971), with an average incidence of 1% of all live births (Demmler, 1991;Stagno et al, 1986). It is estimated that approximately 5% to 10% of infected infants have generalized cytomegalic inclusion disease at birth, with symptoms such as microcephaly, perivascular calcification, and microphthalmia (Bale, 1984;Becroft, 1981;Cinque et al, 1997). Another 10% of infected infants have subclinical congenital infection, and will subsequently suffer from brain disorders, including mental retardation, sensorineural hearing loss, visual disorders, seizures, and epilepsy (Conboy et al, 1986;Pass et al, 1980). In adults, infection with human CMV (HCMV) is usually asymptomatic in immunocompetent hosts, but the virus causes severe or fatal disease in immunocompromised patients (Britt and Alford, 1996). CMV has become the most frequent opportunistic cerebral infection in acquired immunodeficiency syndrome (AIDS), in which it results in CMV encephalitis/ encephalopathy such as ventriculoencephalitis (Morgello et al, 1987;Setinek et al, 1995;Wiley and Nelson, 1988).Because studies of human subjects have obvious limitations, we have developed model systems for brain abnormalities induced by infection of mouse embryos with murine CMV (MCMV) Tsutsui, 1995;Tsutsui et al, 1993). The susceptibility of mice to MCMV in...

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Cytomegalovirus Infection of the Central Nervous System Stem Cells from Mouse Embryo: A Model for Developmental Brain Disorders Induced by Cytomegalovirus

Cited by 73 publications

References 43 publications

Infection with an Endemic Human Herpesvirus Disrupts Critical Glial Precursor Cell Properties

Infection with an Endemic Human Herpesvirus Disrupts Critical Glial Precursor Cell Properties

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

The Amount of Immature Glial Cells in Organotypic Brain Slices Determines the Susceptibility to Murine Cytomegalovirus Infection

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