Modulation of the cytokine network in human adult astrocytes by human herpesvirus-6A

Meeuwsen, S.; Persoon-Deen, Carla; Bsibsi, Malika; Bajramović, Jeffrey J.; Ravid, Rivka; Bolle, Leen De; Noort, Johannes M. van

doi:10.1016/j.jneuroim.2005.03.013

Cited by 38 publications

(36 citation statements)

References 41 publications

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“…CCL5 (RANTES) was shown to be induced by HHV-6A in human astrocytes, endothelial cells, and tonsilar cells (40)(41)(42). Our results in the mouse model are consistent with these data, as HHV-6A also strongly upregulated CCL5 in primary brain cultures as well as other proinflammatory chemokines, including CCL2, CXCL10, and CXCL1.…”

Section: Discussionsupporting

confidence: 89%

“…Therefore, the nonproductive infection observed in these studies may be related to intrinsic characteristics of the infected cell type or potential necessity for prior virus adaptation to murine cells. Finally, when primary murine brain cultures were overlaid with HHV-6A-infected human lymphocytes continuously releasing large quantities of virus, formation of syncytia and production of viral proteins was observed in the murine astrocytes, similar to what has been observed with human astrocytes in an analogous infection environment (40), suggesting permissiveness of murine neural cells to HHV-6A infection when adequate conditions are provided.…”

Section: Discussionsupporting

confidence: 72%

“…However, the absence of consecutive DNA replication in the analyzed cell types suggests abortive or nonproductive infection, possibly due to either the presence of mouse-specific restriction factors or the absence of some human intracellular factors needed for a productive infection. Nevertheless, HHV-6 infection in human cells is not always productive, and an absence of cytopathic effects was reported when primary human astrocytes were infected with cell-free virus (40). Therefore, the nonproductive infection observed in these studies may be related to intrinsic characteristics of the infected cell type or potential necessity for prior virus adaptation to murine cells.…”

Section: Discussionmentioning

confidence: 84%

“…Several studies on human glial cells have suggested that cocultures with productively infected lymphocytes increase the efficiency of the infection (22,27,40). To analyze whether infection also could be amplified in murine cells during continuous contact with cells producing infectious virus, primary brain cultures were overlaid with HHV-6A-infected HSB2 cells.…”

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

confidence: 99%

“…However, HHV-6 is also able to promote inflammation by inducing the development of a Th1 phenotype in T cells (35,36), enhancing the cytotoxicity of NK cells (37), and by increasing the production of proinflammatory cytokines and chemokines in different cell types (38,39). In particular, HHV-6A was shown to induce the expression of CCL5 (RANTES) in human astrocytes, endothelial cells, and tonsilar cells (40)(41)(42). Interestingly, HHV-6 was found to establish latency in the host by integrating into human chromosomes and allowing the virus to be transmitted in the germ line in some individuals (43), which so far is unique among human herpesviruses.…”

mentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 72%

Section: Discussionmentioning

confidence: 84%

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

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

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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Detection of human herpesvirus‐6 in cerebrospinal fluid of patients with encephalitis

Yao

Honarmand²,

Espinosa³

et al. 2009

Annals of Neurology

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Objective Virus infections are the most common causes of encephalitis, a syndrome characterized by acute inflammation of the brain. Over 150 different viruses have been implicated in the pathogenesis of encephalitis, however due to limitations with diagnostic testing, etiologies of over half of the cases remain unknown. Methods To investigate whether HHV-6 is an etiological agent of encephalitis, we examined for evidence of virus infection by determining the presence of viral sequence using PCR and assessed HHV-6 antibody reactivity in the cerebrospinal fluids (CSF) of encephalitis patients with unknown etiology. In a cohort study, we compared virus specific antibody levels in CSF samples of patients with encephalitis, relapsing-remitting MS and other neurologic diseases (OND). Results Our results demonstrated elevated levels of HHV-6 IgG as well as IgM levels in a subset of encephalitis patients compared with OND. Moreover, cell-free viral DNA that is indicative of active infection was detected in 40% (14/35) of encephalitis patients, while no amplifiable viral sequence was found in either relapsing-remitting MS or OND patients. Additionally, a significant correlation between PCR detection and anti-HHV-6 antibody response was also demonstrated. Interpretation Collectively, these results suggested HHV-6 as a possible pathogen in a subset of encephalitis cases.

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Combination of paclitaxel and carboplatin as second‐line therapy for patients with metastatic melanoma

Rao

Holtan

Ingle

et al. 2005

Cancer

110

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Objective Virus infections are the most common causes of encephalitis, a syndrome characterized by acute inflammation of the brain. More than 150 different viruses have been implicated in the pathogenesis of encephalitis; however, because of limitations with diagnostic testing, causative factors of more than half of the cases remain unknown. Methods To investigate whether human herpesvirus‐6 (HHV‐6) is a causative agent of encephalitis, we examined for evidence of virus infection by determining the presence of viral sequence using polymerase chain reaction and assessed HHV‐6 antibody reactivity in the cerebrospinal fluid of encephalitis patients with unknown cause. In a cohort study, we compared virus‐specific antibody levels in cerebrospinal fluid samples of patients with encephalitis, relapsing‐remitting multiple sclerosis, and other neurological diseases. Results Our results demonstrated increased levels of HHV‐6 IgG, as well as IgM levels, in a subset of encephalitis patients compared with other neurological diseases. Moreover, cell‐free viral DNA that is indicative of active infection was detected in 40% (14/35) of encephalitis patients, whereas no amplifiable viral sequence was found in either relapsing‐remitting MS or other neurological diseases patients. In addition, a significant correlation between polymerase chain reaction detection and anti‐HHV‐6 antibody response was also demonstrated. Interpretation Collectively, these results suggested HHV‐6 as a possible pathogen in a subset of encephalitis cases. Ann Neurol 2009;65:257–267

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Modulation of the cytokine network in human adult astrocytes by human herpesvirus-6A

Cited by 38 publications

References 41 publications

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

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

Detection of human herpesvirus‐6 in cerebrospinal fluid of patients with encephalitis

Combination of paclitaxel and carboplatin as second‐line therapy for patients with metastatic melanoma

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