Understanding the molecular mechanism of blood–brain barrier damage in an experimental model of Japanese encephalitis: Correlation with minocycline administration as a therapeutic agent

Mishra, Manoj Kumar; Dutta, Kallol; Saheb, Shaik Khaleelulla; Basu, Anirban

doi:10.1016/j.neuint.2009.07.006

Cited by 69 publications

(69 citation statements)

References 33 publications

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“…The demise of endothelial cells and/or the degradation or dissociation of tight junction proteins can in most cases be attributed to BBB disruption (10,(15)(16)(17)(18). Tight junction proteins, including occludin and claudins that are joined to the cytoskeleton by the cytoplasmic proteins, such as ZOs in particular, play a key role in restricting paracellular permeability.…”

Section: Discussionmentioning

confidence: 99%

“…Although the exact mechanisms of neurotropic virus-associated CNS invasion and encephalitis are yet to be clearly defined, increasing evidence suggests the crucial role of the BBB in controlling viral entry and immune cell infiltration into the nervous tissues. Several clinical and experimental studies demonstrated the dysfunction and/or disruption of the BBB in Japanese encephalitis subjects, and these alterations were positively correlated with the severity of encephalitis (10,(15)(16)(17)(18).…”

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confidence: 99%

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Infection of Pericytes In Vitro by Japanese Encephalitis Virus Disrupts the Integrity of the Endothelial Barrier

Chen

et al. 2014

J Virol

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h Though the compromised blood-brain barrier (BBB) is a pathological hallmark of Japanese encephalitis-associated neurological sequelae, the underlying mechanisms and the specific cell types involved are not understood. BBB characteristics are induced and maintained by cross talk between brain microvascular endothelial cells and neighboring elements of the neurovascular unit. In this study, we show a potential mechanism of disruption of endothelial barrier integrity during the course of Japanese encephalitis virus (JEV) infection through the activation of neighboring pericytes. We found that cultured brain pericytes were susceptible to JEV infection but were without signs of remarkable cytotoxicity. JEV-infected pericytes were found to release biologically active molecules which activated ubiquitin proteasome, degraded zonula occludens-1 (ZO-1), and disrupted endothelial barrier integrity in cultured brain microvascular endothelial cells. Infection of pericytes with JEV was found to elicit elevated production of interleukin-6 (IL-6), which contributed to the aforementioned endothelial changes. We further demonstrated that ubiquitin-protein ligase E3 component n-recognin-1 (Ubr 1) was a key upstream regulator which caused proteasomal degradation of ZO-1 downstream of IL-6 signaling. During JEV central nervous system trafficking, endothelial cells rather than pericytes are directly exposed to cell-free viruses in the peripheral bloodstream. Therefore, the results of this study suggest that subsequent to primary infection of endothelial cells, JEV infection of pericytes might contribute to the initiation and/or augmentation of Japanese encephalitis-associated BBB breakdown in concerted action with other unidentified barrier disrupting factors.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Infection of Pericytes In Vitro by Japanese Encephalitis Virus Disrupts the Integrity of the Endothelial Barrier

Chen

et al. 2014

J Virol

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“…Therefore, modulation of immune cells at the periphery is a prerequisite. In particular, upon modulation of the cells at periphery, JEV generates a favorable microenvironment that facilitates the alteration of BBB integrity [7][8][9][10].The paramount protective function of humoral immunity is well documented in human cases of JEV [11][12][13] as well as in animal models [14][15][16][17] …”

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Japanese encephalitis virus expands regulatory T cells by increasing the expression of PD‐L1 on dendritic cells

et al. 2014

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The mechanisms underlying Japanese encephalitis virus (JEV) pathogenesis need to be thoroughly explored to delineate therapeutic approaches. It is believed that JEV manipulates the innate and adaptive compartments of the host's immune system to evade immune response and cross the blood-brain barrier. The present study was thus designed to investigate the functional modulation of DCs after exposure to JEV and to assess the consequences on CD4 Eur. J. Immunol. 2014Immunol. . 44: 1363Immunol. -1374 Introduction Japanese encephalitis virus (JEV) is the cause of the most dreaded mosquito-borne disease and epidemic viral encephalitis in the world [1][2][3]. The expanding geographical range and JEV's ability to cause devastating epidemics in nonimmune populations demand an urgent effort toward the development of efficient antiviral therapies [4] or of alternate strategies that can reduce JEV immunopathogenesis. A significant number of studies illustrate the importance of crossing the blood-brain barrier (BBB) for pathogenesis and clinical manifestations of JEV infection [5]. JEV induces the activation of endothelial cells to increase the adhesion and transport the infected leukocytes across the BBB [6]. These findings imply that JEV requires escaping immune surveillance at the periphery, until the essential alterations occur at the BBB. Therefore, modulation of immune cells at the periphery is a prerequisite. In particular, upon modulation of the cells at periphery, JEV generates a favorable microenvironment that facilitates the alteration of BBB integrity [7][8][9][10].The paramount protective function of humoral immunity is well documented in human cases of JEV [11][12][13] as well as in animal models [14][15][16][17] Results Replication-competent JEV induces the phenotypic maturation of immature DCsDCs are known to initiate immune responses to invading pathogens. We hypothesized that DCs are privileged targets for modulation by JEV to subvert the immune system and establish successful infection. To evaluate this hypothesis, we first analyzed the effect of JEV on DC activation. The results demonstrate that JEV induces the maturation of DCs at 1 MOI (Fig. 1). The expression of activation markers such as HLA-DR and CD40, and of co-stimulatory molecules such as CD80/B7.1, CD86/B7.2, and CD83, was significantly upregulated on JEV-infected DCs as compared with mock-infected or replication-incompetent JEV-treated DCs ( Fig. 1A-E). We further analyzed the expression of DC-SIGN, which plays a crucial role in DC responses to pathogens [26]. The expression of DC-SIGN was not affected by JEV infection (Fig. 1F), in contrast to observations made with dengue virus, where DC-SIGN expression has been documented to be related to the levels of viral infection [27]. However, a role for DC-SIGN as a possible pattern recognition receptor for JEV cannot be excluded and further investigations are required to explore the role of DC-SIGN in JEV pathogenesis. Interestingly, PD-L1 expression was significantly increased upon infection by re...

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“…ROS has been implicated in the activation of NF-κB, which plays a central role in the expression of iNOS (30). Enhanced iNOS expression in relation to ROS and NF-κB has been demonstrated in several JEV-infected cell lines, including neuroblastoma and microglia (13) as well as in mouse models (31,32). Although DENV2 revealed an increase in iNOS expression, the pathway of iNOS non-radical molecules.…”

Section: Resultsmentioning

confidence: 99%

Dengue Virus-Induced Reactive Oxygen Species Production in Rat Microglial Cells

et al. 2017

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Understanding the molecular mechanism of blood–brain barrier damage in an experimental model of Japanese encephalitis: Correlation with minocycline administration as a therapeutic agent

Cited by 69 publications

References 33 publications

Infection of Pericytes In Vitro by Japanese Encephalitis Virus Disrupts the Integrity of the Endothelial Barrier

Infection of Pericytes In Vitro by Japanese Encephalitis Virus Disrupts the Integrity of the Endothelial Barrier

Japanese encephalitis virus expands regulatory T cells by increasing the expression of PD‐L1 on dendritic cells

Dengue Virus-Induced Reactive Oxygen Species Production in Rat Microglial Cells

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