Japanese encephalitis virus disrupts blood-brain barrier and modulates apoptosis proteins in THBMEC cells

Al-Obaidi, Mazen M. Jamil; Bahadoran, Azadeh; Har, Lee Sau; Wang, Seok Mui; Jayakumar, R.; Zandi, Keivan; Manikam, Rishya; Sekaran, Shamala Devi

doi:10.1016/j.virusres.2017.02.012

Cited by 31 publications

(38 citation statements)

References 91 publications

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“…Here we show using an in vitro human co-culture BBB model that cells within the BBB themselves generate this strong, local inflammatory response. Interestingly, a recent study suggests that JEV interferes with the apoptotic pathways in transfected human brain microvascular endothelial cells, perhaps to prolong the period during which viral replication can occur ( Al-Obaidi et al, 2017 ). A previous clinical study and work from a macaque model from our group ( Winter et al, 2004 ; Myint et al, 2014 ), and several studies on mouse models ( Kim et al, 2016 ; Shukla et al, 2016 ; Biswas et al, 2010 ; Chen et al, 2012 ; Gupta et al, 2010 ) have shown the importance of pro-inflammatory mediators during JEV infection.…”

Section: Discussionmentioning

confidence: 99%

Brain microvascular endothelial-astrocyte cell responses following Japanese encephalitis virus infection in an in vitro human blood-brain barrier model

Patabendige

Michael

Craig

et al. 2018

Molecular and Cellular Neuroscience

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Japanese encephalitis virus (JEV) remains a leading cause of encephalitis, globally, which continues to grow in importance despite the availability of vaccines. Viral entry into the brain can occur via the blood-brain barrier (BBB), and inflammation at the BBB is a common final pathway in many brain infections. However, the role of the BBB during JEV infection and the contribution of the endothelial and astrocytic cell inflammation in facilitating virus entry into the brain are incompletely understood. We established a BBB model using human brain endothelial cells (HBECs) and human astrocytes. HBECs are polarised, and therefore the model was inoculated by JEV from the apical side to simulate the in vivo situation. The effects of JEV on the BBB permeability and release of inflammatory mediators from both apical and basolateral sides, representing the blood and the brain side respectively were investigated. JEV infected HBECs with limited active virus production, before crossing the BBB and infecting astrocytes. Control of JEV production by HBECs was associated with a significant increase in permeability, and with elevation of many host mediators, including cytokines, chemokines, cellular adhesion molecules, and matrix metalloproteases. When compared to the controls, significantly higher amounts of mediators were released from the apical side as opposed to the basolateral side. The increased release of mediators over time also correlated with increased BBB permeability. Treatment with dexamethasone led to a significant reduction in the release of interleukin 6 (IL6), C-C motif chemokine ligand 5 (CCL5) and C-X-C motif chemokine ligand 10 (CXCL10) from the apical side with a reduction in BBB disruption and no change in JEV production. The results are consistent with the hypothesis that JEV infection of the BBB triggers the production of a range of host mediators from both endothelial cells and astrocytes, which control JEV production but disrupt BBB integrity thus allowing virus entry into the brain. Dexamethasone treatment controlled the host response and limited BBB disruption in the model without increasing JEV production, supporting a re-investigation of its use therapeutically.

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Section: Discussionmentioning

confidence: 99%

Brain microvascular endothelial-astrocyte cell responses following Japanese encephalitis virus infection in an in vitro human blood-brain barrier model

Patabendige

Michael

Craig

et al. 2018

Molecular and Cellular Neuroscience

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“…Nevertheless in mice, the BBB disrupts only after viral neuroinvasion [ 16 ] indicating that neural infection is not necessary a consequence of the breakdown of the BBB, but the other way around. Interestingly, JEV productively infects rodent microvascular brain endothelial cells [ 39 ] that may be functionally affected in terms of their role for the BBB [ 21 , 39 , 40 ]. As these form the blood-brain barrier, this may represent a possible way of JEV transmission to brain tissue cells [ 41 ], after which the virus could infect pericytes [ 42 ] and astrocytes [ 39 , 43 ].…”

Section: Tropism and Kinetics Of Viral Replicationmentioning

confidence: 99%

Regulation of inflammation in Japanese encephalitis

Lannes

Summerfield

Filgueira

2017

J Neuroinflammation

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Background: Uncontrolled inflammatory response of the central nervous system is a hallmark of severe Japanese encephalitis (JE). Although inflammation is necessary to mount an efficient immune response against virus infections, exacerbated inflammatory response is often detrimental. In this context, cells of the monocytic lineage appear to be important forces driving JE pathogenesis. Main body: Brain-infiltrating monocytes, macrophages and microglia play a major role in central nervous system (CNS) inflammation during JE. Moreover, the role of inflammatory monocytes in viral neuroinvasion during JE and mechanisms of cell entry into the CNS remains unclear. The identification of cellular and molecular actors in JE inflammatory responses may help to understand the mechanisms behind excessive inflammation and to develop therapeutics to treat JE patients. This review addresses the current knowledge about mechanisms of virus neuroinvasion, neuroinflammation and therapeutics critical for JE outcome. Conclusion: Understanding the regulation of inflammation in JE is challenging. Elucidation of the remaining open questions will help to the development of therapeutic approaches avoiding detrimental inflammatory responses in JE.

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“…One is to disrupt the barrier integrity. The Rubella virus, cytomegalovirus (CMV), the Human immunodeficiency virus type 1 (HIV-1), the West Nile virus (WNV), the Japanese encephalitis virus (JEV), and herpes viruses are known to breach the placental barriers to reach the CNS (Roe et al, 2012(Roe et al, , 2014Coyne and Lazear, 2016;Al-Obaidi et al, 2017;Leibrand et al, 2017;Mittal et al, 2017). The other is through transcytosis.…”

Section: Introductionmentioning

confidence: 99%

The Mechanism of the Zika Virus Crossing the Placental Barrier and the Blood-Brain Barrier

Chiu¹,

Chu²,

Liao³

et al. 2020

Front. Microbiol.

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Zika virus (ZIKV) infection causes severe neurological symptoms in adults and fetal microcephaly and the virus is detected in the brain of microcephaly and meningoencephalitis patient. However, the mechanism of ZIKV crossing the physiological barrier to the central nervous systems (CNS) remains elusive. The placental barrier and the blood brain barrier (BBB) protect the fetus from pathogens and ensure healthy brain development during pregnancy. In this study, we used human placenta trophoblasts cells (JEG-3) and human brain-derived endothelial cells (hCMEC/D3) as in vitro models of the physiological barriers. Results showed that ZIKV could infect JEG-3 cells effectively and reduce the amounts of ZO-1 and occludin between adjacent cells by the proteasomal degradation pathway, suggesting that the permeability of the barrier differentially changed in response to ZIKV infection, allowing the virus particle to cross the host barrier. In contrast, ZIKV could infect hCMEC/D3 cells without disrupting the BBB barrier permeability and tight junction protein expression. Although no disruption to the BBB was observed during ZIKV infection, ZIKV particles were released on the basal side of the BBB model and infected underlying cells. In addition, we observed that fluorescence-labeled ZIKV particles could cross the in vitro placenta barrier and BBB model by transcytosis and the action of transcytosis could be blocked by either low temperature or pharmacological inhibitors of endocytosis. In summary, the ZIKV uses a cell-type specific paracellular pathway to cross the placenta monolayer barrier by disrupting cellular tight junction. In addition, the ZIKV can also cross both the placenta barrier and the BBB by transcytosis. Our study provided new insights into on the mechanism of the cellular barrier penetration of ZIKV particles.

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Japanese encephalitis virus disrupts blood-brain barrier and modulates apoptosis proteins in THBMEC cells

Cited by 31 publications

References 91 publications

Brain microvascular endothelial-astrocyte cell responses following Japanese encephalitis virus infection in an in vitro human blood-brain barrier model

Brain microvascular endothelial-astrocyte cell responses following Japanese encephalitis virus infection in an in vitro human blood-brain barrier model

Regulation of inflammation in Japanese encephalitis

The Mechanism of the Zika Virus Crossing the Placental Barrier and the Blood-Brain Barrier

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