Disordered migration and loss of virus-infected neuronal cells in developing mouse brains infected with murine cytomegalovirus

Shinmura, Yuichiro; Kosugi, Isao; Aiba-Masago, Sonomi; Baba, Satoshi; Luo, Yiwen; Tsutsui, Yoshihiro

doi:10.1007/s004010050651

Cited by 56 publications

(50 citation statements)

References 23 publications

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“…For instance, virus-mediated ⌬N-p73␣ accumulation can be predicted to immortalize Cajal-Retzius cells and to induce abnormal cortical migration with subsequent lissencephaly and/or epilepsy-like syndromes. In developing mice, indeed, mCMV was found to alter cortical neuronal migration (30), and in humans, epilepsy and disorders of cortical development in children with HCMV congenital infection have been described (31). On the other hand, by the induction of drug resistance and alteration of programmed cell death, cytomegalovirus infection may be implicated in the etiology and/or progression of malignancies such as neuroblastoma (4,32).…”

Section: Discussionmentioning

confidence: 99%

Human Cytomegalovirus Induces Drug Resistance and Alteration of Programmed Cell Death by Accumulation of ΔN-p73α

Allart¹,

Martin²,

Détraves³

et al. 2002

Journal of Biological Chemistry

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Intrauterine transmission of human cytomegalovirus (HCMV) to the fetus following primary infection in early and late pregnancy usually results in severe neurological handicaps and sensorineural hearing loss with typical migrational anomalies, optic atrophy, disturbed myelination, cerebella hypoplasia, microcephaly, hydrocephaly, and lissencephaly. Recently, evidences raised from the phenotype of p73-deficient mice show that an association may exist between the expression of the TP53 homologous gene and HCMV tropism in the brain, suggesting an implication of p73 in viral persistence. In this study, we demonstrated that HCMV-mediated inhibition of apoptosis only occurs in p73-expressing cells. Upon infection, an accumulation of ⌬N-p73␣ isoforms was observed in HCMV-infected p73-positive cells. This phenomenon was shown to be responsible for the subsequent acquired resistance to apoptosis of infected cells. Inhibition of apoptosis in p73-positive cells by HCMV may thus contribute both to virus persistency and abnormal nervous cell survival. This finding provides the first molecular basis for HCMV-associated abnormal embryonic development and neurological defects in newborns.Human cytomegalovirus (HCMV), 1 a ␤-herpes virus, is harmless to most immunocompetent people. However, HCMV is responsible for serious illness and death in immunocompromised hosts such as AIDS patients, as well as patients receiving immunosuppressive treatment following organ transplantation. Cytomegalovirus infection is the most common congenital viral infection and carries a high risk of long term morbidity and mortality. Intrauterine transmission to the unprotected fetus in early and late pregnancy usually results in death or in severe neurological defects including sensorineural hearing loss, optic atrophy, disturbed myelination, cerebella hypoplasia, microcephaly, hydrocephaly, and lissencephaly (for reviews, see Refs. 1 and 2). How morphological and functional disorders develop is unclear since little is known about mechanisms underlying the pathogenicity of the virus.Apoptosis is an important process participating in the formation of organs and tissues during embryogenesis and in the clearance of abnormal or misfunctioning cells in the body. At any stages of life, interference with this process is predicted to be damaging for organisms. In the mouse developing brain, surprisingly, murine cytomegalovirus (mCMV) was found to induce apoptosis in non-infected cells, whereas a blocking of apoptosis occurred in infected mature neurons (3). Similar results were obtained with human neuroblastoma cells, which become "immortalized" and resistant to cytotoxic stress following HCMV infection (4). As with many other viruses, HCMV has developed strategies to inhibit apoptosis of infected cells, thus escaping from immune clearance, promoting abnormal cell survival, and favoring viral persistence. Some reports discuss possible mechanisms by which HCMV can block apoptosis. HCMV proteins can directly interact with the tumor suppressor p53 and interfere wit...

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Section: Discussionmentioning

confidence: 99%

Human Cytomegalovirus Induces Drug Resistance and Alteration of Programmed Cell Death by Accumulation of ΔN-p73α

Allart¹,

Martin²,

Détraves³

et al. 2002

Journal of Biological Chemistry

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“…MCMV inoculation into lateral ventricles at embryonic days 14.5 and 15.5 causes a disturbance in neuronal migration and a marked loss of neurons in postnatal brains. 57 What could be the mechanism(s) responsible for the altered brain development observed in CMV infection? Although the abnormalities are temporally related with MCMV replication in the CNS, there is a sharp contrast between focal distribution of the paucity of virus-infected cells and global defects in brain morphogenesis.…”

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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“…93 Conversely, interdependent host factors such as the developmental stage at infection, expression of viral entry receptors, and immune responses determine the cell types infected and the ultimate pathology engendered by the virus. 57 An example of such pathology is aberrant neuronal migration, which has been demonstrated in experimental hosts after prenatal or neonatal infection with influenza virus, 94,95 murine cytomegalovirus, 96 mumps virus 97 and parvovirus. 98 The mechanisms by which some viruses interfere with the cellular machinery governing neuronal migration has not been well characterized and is highly amenable to study in animal models.…”

Section: Modeling Mechanisms: Defining the Questionsmentioning

confidence: 99%

Schizophrenia and viral infection during neurodevelopment: a focus on mechanisms

Pearce

2001

Mol Psychiatry

135

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The task of defining schizophrenia pathogenesis has fascinated and frustrated researchers for nearly a century. In recent years, unprecedented advances from diverse fields of study have given credence to both viral and developmental theories. This review considers possible mechanisms by which viral and developmental processes may interact to engender schizophrenia. Many of the current controversies in schizophrenia pathogenesis are reviewed in light of the viral hypothesis, including: epidemiological findings and the role of a genetic diathesis, phenotype heterogeneity, abnormalities in excitatory and inhibitory neurotransmitter systems, anomalous cerebral latereralization, and static vs progressive disease. The importance of animal models in elucidating the impact of viral infections on developing neurons is illustrated by recent studies in which neonatal rats are infected with lymphocytic choriomeningitis virus in order to examine alterations in hippocampal circuitry. Finally, consideration is given to a new hypothesis that some cases of schizophrenia could be instigated by a viral infection that disrupts developing inhibitory circuits, consequently unleashing glutamatergic neurotransmission leading to selective excitotoxicity, and a degenerative disease course. Molecular Psychiatry (2001) 6, 634-646.

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Disordered migration and loss of virus-infected neuronal cells in developing mouse brains infected with murine cytomegalovirus

Cited by 56 publications

References 23 publications

Human Cytomegalovirus Induces Drug Resistance and Alteration of Programmed Cell Death by Accumulation of ΔN-p73α

Human Cytomegalovirus Induces Drug Resistance and Alteration of Programmed Cell Death by Accumulation of ΔN-p73α

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

Schizophrenia and viral infection during neurodevelopment: a focus on mechanisms

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