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

Dietrich, Jöerg; Blumberg, Benjamin M.; Roshal, Mikhail; Baker, Jeffrey V.; Hurley, Sean D.; Mayer-Pröschel, Margot; Mock, David J.

doi:10.1523/jneurosci.5584-03.2004

Cited by 66 publications

(49 citation statements)

References 76 publications

(73 reference statements)

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“…In vitro studies suggest that the two variants of HHV-6 have different patterns of infection and tropism for glial cell subtypes. Though both variants can grow in glial precursor cells (12), human primary glial cells (3,20), and glia cell lines (10,42), infection with HHV-6A has been reported to be associated with CPE and viral DNA detection (10), consistent with a number of clinical observations suggesting a greater neurotropism for this viral variant (19,22,34).…”

supporting

confidence: 68%

Variant-Specific Tropism of Human Herpesvirus 6 in Human Astrocytes

Donati

Martinelli

Cassiani-Ingoni

et al. 2005

J Virol

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Though first described as a lymphotropic virus, human herpesvirus 6 (HHV-6) is highly neuropathogenic. Two viral variants are known: HHV-6A and HHV-6B. Both variants can infect glial cells and have been differentially associated with central nervous system diseases, suggesting an HHV-6 variant-specific tropism for glial cell subtypes. We have performed infections with both viral variants in human progenitor-derived astrocytes (HPDA) and monitored infected cell cultures for cytopathic effect (CPE), intra-and extracellular viral DNA load, the presence of viral particles by electronic microscopy, mRNA transcription, and viral protein expression. HHV-6A established a productive infection with CPE, visible intracellular virions, and high virus DNA loads. HHV-6B-infected HPDA showed no morphological changes, intracellular viral particles, and decreasing intra-and extracellular viral DNA over time. After long-term passage, HHV-6B-infected HPDA had stable but low levels of intracellular viral DNA load with no detectable viral mRNA. Our results demonstrate that HHV-6A and HHV-6B have differential tropisms and patterns of infection for HPDA in vitro, where HHV-6A results in a productive lytic infection. In contrast, HHV-6B was associated with a nonproductive infection. These findings suggest that HHV-6 variants might be responsible for specific infection patterns in glial cells in vivo. Astrocytes may be an important reservoir for this virus in which differential tropism of HHV-6A and HHV-6B may be associated with different disease outcomes.

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supporting

confidence: 68%

Variant-Specific Tropism of Human Herpesvirus 6 in Human Astrocytes

Donati

Martinelli

Cassiani-Ingoni

et al. 2005

J Virol

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“…In fact neuroleptics have been shown to stimulate proliferation and development of oligodendrocyte progenitors [34][35][36] rather than decrease them. However, oligodendrocyte precursors are sensitive to environmental stress signals such as oxidative stress, glutamate-relative excitotoxicity 37 and persistent viral infection 38. all of which have been implicated in the eitiology of schizophrenia.…”

Section: Discussionmentioning

confidence: 99%

Abnormalities in oligodendrocyte clusters in the inferior parietal cortex in schizophrenia are associated with insight

Kolomeets

Vostrikov

2013

Eur. J. Psychiat.

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“…As HHV-6 is known to be neurotropic in humans and to infect both human astrocytes and oligodendrocytes (22)(23)(24)(25), we next analyzed the permissiveness of primary brain glial cultures, which mostly contain astrocytes and, to a lesser extent, oligodendrocytes and microglial cells (data not shown), to HHV-6 infection. These cultures were obtained from either CD46-cyt1 mice, expressing the cyt1 isoform of CD46, or wild-type littermate con-trols (Fig.…”

Section: Infection Of Cd46-transfected Murine Lymphocyte Lines With Hmentioning

confidence: 99%

“…CD46 expression in humans is ubiquitous (19); therefore, it provides a wide range of potentially susceptible cell types for HHV-6 infection. Although lymphocytes are known as the main target cells, several CNS cell types, including astrocytes and oligodendrocytes, have been successfully infected by HHV-6A and, with lower efficiency, by HHV-6B (20)(21)(22)(23)(24)(25)(26)(27). Recently, CD134 (OX40), a member of the tumor necrosis factor (TNF) receptor superfamily that was expressed on activated T lymphocytes, has been identified as a receptor molecule for HHV-6B (28).…”

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confidence: 99%

Human Herpesvirus 6A Infection in CD46 Transgenic Mice: Viral Persistence in the Brain and Increased Production of Proinflammatory Chemokines via Toll-Like Receptor 9

Reynaud

Jégou

Welsch

et al. 2014

J Virol

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Human herpesvirus 6 (HHV-6) is widely spread in the human population and has been associated with several neuroinflammatory diseases, including multiple sclerosis. To develop a small-animal model of HHV-6 infection, we analyzed the susceptibility of several lines of transgenic mice expressing human CD46, identified as a receptor for HHV-6. We showed that HHV-6A (GS) infection results in the expression of viral transcripts in primary brain glial cultures from CD46-expressing mice, while HHV-6B (Z29) infection was inefficient. HHV-6A DNA persisted for up to 9 months in the brain of CD46-expressing mice but not in the nontransgenic littermates, whereas HHV-6B DNA levels decreased rapidly after infection in all mice. Persistence in the brain was observed with infectious but not heat-inactivated HHV-6A. Immunohistological studies revealed the presence of infiltrating lymphocytes in periventricular areas of the brain of HHV-6A-infected mice. Furthermore, HHV-6A stimulated the production of a panel of proinflammatory chemokines in primary brain glial cultures, including CCL2, CCL5, and CXCL10, and induced the expression of CCL5 in the brains of HHV-6A-infected mice. HHV-6A-induced production of chemokines in the primary glial cultures was dependent on the stimulation of toll-like receptor 9 (TLR9). Finally, HHV-6A induced signaling through human TLR9 as well, extending observations from the murine model to human infection. Altogether, this study presents a first murine model for HHV-6A-induced brain infection and suggests a role for TLR9 in the HHV-6A-initiated production of proinflammatory chemokines in the brain, opening novel perspectives for the study of virus-associated neuropathology. IMPORTANCEHHV-6 infection has been related to neuroinflammatory diseases; however, the lack of a suitable small-animal infection model has considerably hampered further studies of HHV-6-induced neuropathogenesis. In this study, we have characterized a new model for HHV-6 infection in mice expressing the human CD46 protein. Infection of CD46 transgenic mice with HHV-6A resulted in long-term persistence of viral DNA in the brains of infected animals and was followed by lymphocyte infiltration and upregulation of the CCL5 chemokine in the absence of clinical signs of disease. The secretion of a panel of chemokines was increased after infection in primary murine brain glial cultures, and the HHV-6-induced chemokine expression was inhibited when TLR9 signaling was blocked. These results describe the first murine model for HHV-6A-induced brain infection and suggest the importance of the TLR9 pathway in HHV-6A-initiated neuroinflammation.

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

Cited by 66 publications

References 76 publications

Variant-Specific Tropism of Human Herpesvirus 6 in Human Astrocytes

Variant-Specific Tropism of Human Herpesvirus 6 in Human Astrocytes

Abnormalities in oligodendrocyte clusters in the inferior parietal cortex in schizophrenia are associated with insight

Human Herpesvirus 6A Infection in CD46 Transgenic Mice: Viral Persistence in the Brain and Increased Production of Proinflammatory Chemokines via Toll-Like Receptor 9

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