Cytomegalovirus Infections of the Nervous System

Cinque, Paola; Marenzi, Roberta; Ceresa, Daniela

doi:10.1159/000150536

Cited by 56 publications

(63 citation statements)

References 89 publications

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“…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).…”

Section: Discussionmentioning

confidence: 99%

“…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).…”

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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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Section: Discussionmentioning

confidence: 99%

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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“…Among the herpes viruses, HSV1, HSV2, cytomegalovirus (CMV), Epstein-Barr virus (EBV), varicella-zoster virus (VZV) and human herpes virus 6 (HHV6) have neurotrophic potential. 12 The central nervous system infection of CMV, 14 EBV 15 and VZV 16 in immunocompetent persons is rare. HSV2 infection of brain usually occurs in neonates.…”

Section: Introductionmentioning

confidence: 99%

Brain morphological changes associated with exposure to HSV1 in first-episode schizophrenia

et al. 2006

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Infectious agents have been proposed as one of the risk factors for schizophrenia. However, the data on the association of infectious agents with in vivo brain changes are scant. We evaluated the association of serological evidence of exposure to herpes simplex virus 1 (HSV1) with in vivo brain structural variations among first-episode antipsychotic-naive schizophrenia/ schizoaffective disorder patients and control subjects. We assayed HSV1 immunoglobulin G (IgG) antibody in serum samples from 30 patients and 44 healthy subjects and obtained structural magnetic resonance imaging scans from the same individuals. There were proportionately more patients with elevated HSV1 antibody ratios than healthy comparison subjects (v 2 = 3.98, 1 df, P = 0.046) and patients had significantly higher HSV1 IgG antibody ratios compared with healthy subjects. Using optimized voxel-based morphometry, we examined diagnosis by HSV1 serological status interaction followed by within-and betweengroup comparison across the serological status. We observed a diagnosis by HSV1 serological status interaction and a significant main effect of HSV1 serological status in the prefrontal gray matter. Patients exposed to HSV1 had decreased gray matter in Brodmann area 9 (dorsolateral prefrontal cortex) and 32 (anterior cingulate cortex) compared with patients without serological evidence of exposure to HSV1. HSV1-associated differences in brain structure were not detected among healthy subjects. These findings suggest that HSV1 exposure in schizophrenia is associated with specific regional gray matter differences that may not be attributable to medications, illness chronicity or comorbid substance use. This study provides suggestive evidence for a link between HSV1 exposure and some of the cerebral morphological changes often reported in schizophrenia.

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“…It is estimated that approximately 5 to 10% of infected infants have severe brain damage (2,4,7,13). Another nearly 10% of infected infants have subclinical congenital infection and will subsequently have brain disorders, including mental retardation, seizures, and epilepsy (9,33).…”

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confidence: 99%

Reactivation of Latent Cytomegalovirus Infection in Mouse Brain Cells Detected after Transfer to Brain Slice Cultures

Tsutsui

Kawasaki

Kosugi

2002

J Virol

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Cytomegalovirus (CMV) is the most significant infectious cause of brain disorders in humans involving the developing brain. It is hypothesized that the brain disorders occur after recurrent reactivation of the latent infection in some kinds of cells in the brains. In order to test this hypothesis, we examined the reactivation of latent murine CMV (MCMV) infection in the mouse brain by transfer to brain slice culture. We infected neonatal and young adult mice intracerebrally with recombinant MCMV in which the lacZ gene was inserted into a late gene. The brains were removed 6 months after infection and used to prepare brain slices that were then cultured for up to 4 weeks. Reactivation of latent infection in the brains was detected by ␤-galactosidase (␤-Gal) staining to assess ␤-galactosidase expression. Viral replication was also confirmed by the plaque assay. Reactivation was observed in about 75% of the mice infected during the neonatal period 6 months after infection. Unexpectedly, reactivation was also observed in 75% of mice infected as young adults, although the infection ratio in the brain slices was significantly lower than that in neonatally infected mice. ␤-Gal-positive cells were observed in marginal regions of the brains or immature neural cells in the ventricular walls. Immunohistochemical staining showed that the ␤-Gal-positive reactivated cells were neural stem or progenitor cells. These results suggest that brain disorders may occur long after infection by reactivation of latent infection in the immature neural cells in the brain.

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Cytomegalovirus Infections of the Nervous System

Cited by 56 publications

References 89 publications

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

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

Brain morphological changes associated with exposure to HSV1 in first-episode schizophrenia

Reactivation of Latent Cytomegalovirus Infection in Mouse Brain Cells Detected after Transfer to Brain Slice Cultures

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