Hepatitis C Virus Infects the Endothelial Cells of the Blood-Brain Barrier

Fletcher, Nicola F.; Wilson, Garrick K.; Murray, Jacinta; Hu, Ke; Lewis, Alan P.; Reynolds, Gary; Stamataki, Zania; Meredith, Luke W.; Rowe, Ian; Luo, Guangxiang; Lopez-Ramirez, Miguel Alejandro; Baumert, Thomas F.; Weksler, Babette B.; Couraud, Pierre‐Olivier; Kim, Kwang Sik; Romero, Ignacio A.; Jopling, Catherine L.; Morgello, Susan; Balfe, Peter; McKeating, Jane A.

doi:10.1053/j.gastro.2011.11.028

Cited by 214 publications

(172 citation statements)

References 46 publications

(57 reference statements)

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“…This major TJ protein that plays an important role in TJ integrity has a low expression in cerebrovascular endothelium. In agreement with other studies,30, 31 protein expression of CLDN1 in the intact control (NC) HBMECs was extremely low and almost undetectable either with immunofluorescence staining or Western blot. Similar to NC samples, in the OGD cells transfected with control oligonucleotides (CLDN1 distribution and expression was similar in OGD/IC and OGD/MC control samples), CLDN1 distribution was mostly cytoplasmic and the expression was weak (Figure 5A, OGD/IC panel).…”

Section: Resultssupporting

confidence: 93%

“…While CLDN5 is highly expressed in the brain endothelium, CLDN1 expression in cerebral capillaries is low and was only confirmed to be present in human, rat, and sheep BBB 3, 30, 31. Regardless of the low expression, CLDN1 function in human brain capillaries is critical for the maintenance of the BBB integrity during neuroinflammation and brain tumor 29, 44.…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of MicroRNA‐155 Supports Endothelial Tight Junction Integrity Following Oxygen‐Glucose Deprivation

Peña-Philippides

Gardiner

Caballero-Garrido

et al. 2018

JAHA

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BackgroundBrain microvascular endothelial cells form a highly selective blood brain barrier regulated by the endothelial tight junctions. Cerebral ischemia selectively targets tight junction protein complexes, which leads to significant damage to cerebral microvasculature. Short noncoding molecules called microRNAs are implicated in the regulation of various pathological states, including endothelial barrier dysfunction. In the present study, we investigated the influence of microRNA‐155 (miR‐155) on the barrier characteristics of human primary brain microvascular endothelial cells (HBMECs).Methods and ResultsOxygen‐glucose deprivation was used as an in vitro model of ischemic stroke. HBMECs were subjected to 3 hours of oxygen‐glucose deprivation, followed by transfections with miR‐155 inhibitor, mimic, or appropriate control oligonucleotides. Intact normoxia control HBMECs and 4 oxygen‐glucose deprivation–treated groups of cells transfected with appropriate nucleotide were subjected to endothelial monolayer electrical resistance and permeability assays, cell viability assay, assessment of NO and human cytokine/chemokine release, immunofluorescence microscopy, Western blot, and polymerase chain reaction analyses. Assessment of endothelial resistance and permeability demonstrated that miR‐155 inhibition improved HBMECs monolayer integrity. In addition, miR‐155 inhibition significantly increased the levels of major tight junction proteins claudin‐1 and zonula occludens protein‐1, while its overexpression reduced these levels. Immunoprecipitation and colocalization analyses detected that miR‐155 inhibition supported the association between zonula occludens protein‐1 and claudin‐1 and their stabilization at the HBMEC membrane. Luciferase reporter assay verified that claudin‐1 is directly targeted by miR‐155.ConclusionsBased on these results, we conclude that miR‐155 inhibition–induced strengthening of endothelial tight junctions after oxygen‐glucose deprivation is mediated via its direct target protein claudin‐1.

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Section: Resultssupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Inhibition of MicroRNA‐155 Supports Endothelial Tight Junction Integrity Following Oxygen‐Glucose Deprivation

Peña-Philippides

Gardiner

Caballero-Garrido

et al. 2018

JAHA

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“…These cell lines were the first extra-hepatic cells that sustain HCV infection without ectopic expression of cellular factor required for viral entry (Lindenbach 2010). HCV tropism for the brain is further supported by a recent study by Fletcher et al demon strating productive HCV infection of brain microvascular en dothelial cells (BMEC), a major component of the blood/brain bar rier (Fletcher, Wilson et al 2012). In this study, two independent de rived brain microvascular endothelial cell lines were described to ex press all HCV receptor molecules and could be infected with HCVpp and HCVcc.…”

Section: Permissive Host Cellsmentioning

confidence: 63%

Cell Culture Systems for Hepatitis C Virus

Steinmann

Pietschmann

2013

Current Topics in Microbiology and Immunology

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Due to the obligatory intracellular life style of viruses, cell culture systems for efficient viral propagation are crucial to obtain a detailed understanding of the virus host cell interaction. For hepatitis C virus (HCV) the development of permissive and authentic culture models has been and continues to be a challenging task. The first ef forts to culture HCV had limited success and range back to before the virus was molecularly cloned in 1989. Since then several major breakthroughs have gradually overcome limitations in culturing the virus and sequentially permitted analysis of viral RNA replication, cell entry and ultimately the complete replication cycle in cultured cells in 2005. Until today, basic and applied HCV research greatly benefit from these tremendous efforts which spurred multiple com plementary cell based model systems for distinct steps of the HCV replication cycle. When used in combination they now permit deep insights into the fascinating biology of HCV and its interplay with the host cell. In fact drug development has been much facilitated and our understanding of the molecular determinants of HCV replication has grown in parallel to these advances. Building on this ground work and further refining our cellular models to better mimic the ar chitecture, polarization and differentiation of natural hepatocytes should reveal novel unique aspects of HCV replication. Ultimately, models to culture primary HCV isolates across all genotypes may teach us important new lessons about viral functional adaptations that have evolved in exchange with its human host and that may ex plain the variable natural course of hepatitis C.

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“…35 What is more, SPECT studies have shown decreased binding capacity of a serotonin transporter in the mesencephalon and/or dopamine transporter in the striatum in 14 out of 20 examined patients independently of their PCR status. 34 Patients with disturbed monoamine transporter binding capacity achieved significantly worse results upon psychometric testing (especially with regard to mood and cognition) compared to the control group. Hence, the disturbances of monoaminergic neurotransmission may be an important factor of the CNS dysfunction in the course of HCV infection.…”

Section: Etiopathogenesis Of Cns Impairmentmentioning

confidence: 93%

“…That study suggests that HCV may disrupt the integrity of the blood/brain barrier in vivo as well. 34 The presence and replication of HCV has been found also in BMEC which indicates that the blood/brain barrier may be directly involved in HCV brain pathogenesis. 1,3 The secondary effects of a chronic inflammatory systemic process and the role of cytokines, which are presumably mediating the cognitive dysfunction, is an important part of the etiopathogenesis of the CNS pathology in the course of hepatitis C.…”

Section: Etiopathogenesis Of Cns Impairmentmentioning

confidence: 99%

The neuropsychiatric aspect of the HCV infection

Więdłocha¹,

Marcinowicz²,

Sokalla³

et al. 2017

Adv Clin Exp Med

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HCV infection is significantly more prevalent in the population of psychiatric patients, drug addicts and people tending to undertake risky sexual behaviors than in the general population. This article presents a spectrum of psychopathological symptoms and psychological dysfunctions, an outline of current theories on the neuropathology and psychiatric aspects of HCV infection treatment. The unspecific character of the psychopathological symptoms in the HCV infection makes the process of thorough diagnostics and adequate treatment difficult, thus the specific and characteristic features have been emphasized. The aim of this review is to shed light not only on the basic information concerning CNS pathology but also on the conclusions emerging from the studies of different authors, of various methodology, in diverse study groups and also to investigate current topics of research. The results of neuroimaging studies have been presented as well. Attention has also been dedicated separately to specific issues, like psychiatric aspects of co-infection with HCV and HIV viruses, the chronic fatigue in the course of HCV infection, the influence of substance use disorders and difficulties encountered during treatment with interferon. Undiagnosed psychiatric disorders, not only inevitably decrease the already rather low quality of life but also cause non-adherence with recommendations and medications regimes, contributing to a worse treatment outcome. Finally, the above disorders, when left untreated, result in higher rates of risk-taking behaviors among the infected, thus imposing a danger not only to patients themselves but also to the healthy population.

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Hepatitis C Virus Infects the Endothelial Cells of the Blood-Brain Barrier

Cited by 214 publications

References 46 publications

Inhibition of MicroRNA‐155 Supports Endothelial Tight Junction Integrity Following Oxygen‐Glucose Deprivation

Inhibition of MicroRNA‐155 Supports Endothelial Tight Junction Integrity Following Oxygen‐Glucose Deprivation

Cell Culture Systems for Hepatitis C Virus

The neuropsychiatric aspect of the HCV infection

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