Highly permissive infection of microglial cells by Japanese encephalitis virus: a possible role as a viral reservoir

Thongtan, Thananya; Cheepsunthorn, Poonlarp; Chaiworakul, Voravasa; Rattanarungsan, Chutima; Wikan, Nitwara; Smith, Duncan R.

doi:10.1016/j.micinf.2009.09.013

Cited by 62 publications

(59 citation statements)

References 27 publications

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“…Cathepsin L-mediated processing of the capsid protein appears to play a role in JEV replication in macrophages, since mutant virus resistant to cleavage by the protease has impaired growth in macrophage but not fibroblast or mosquito cell lines (Mori et al, 2007). Microglia are a brain-resident macrophage cell population, which can be infected with JEV for prolonged periods without morphological alteration, suggesting that microglia might serve as a reservoir for viral persistence in the CNS (Thongtan et al, 2010). Local immune responses initiated by microglial cells may provide protection against JEV infection of the CNS.…”

Section: Cellular Factors Chemokines and Cytokinesmentioning

confidence: 99%

Immunobiology of Japanese Encephalitis Virus

Larena¹,

Lobigs²

2011

Flavivirus Encephalitis

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Section: Cellular Factors Chemokines and Cytokinesmentioning

confidence: 99%

Immunobiology of Japanese Encephalitis Virus

Larena¹,

Lobigs²

2011

Flavivirus Encephalitis

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“…Microglia have been implicated as a viral reservoir for CNS infection, owing to the high viral titer and persistency of JEV infection in these cells [Thongtan et al, 2010]. The parenchymal microglia comprises approximately 12% of the cells in the brain and these cells are important for monitoring the CNS environment and restoring homeostasis after the CNS injury.…”

Section: Introductionmentioning

confidence: 99%

Characterization of putative Japanese encephalitis virus receptor molecules on microglial cells

Thongtan

Wikan

Wintachai

et al. 2012

Journal of Medical Virology

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Japanese encephalitis virus (JEV) a mosquito-borne flavivirus is a major cause of viral encephalitis in Asia. While the principle target cells for JEV in the central nervous system are believed to be neurons, microglia are activated in response to JEV and have been proposed to act as a long lasting virus reservoir. Viral attachment to a host cell is the first step of the viral entry process and is a critical mediator of tissue tropism. This study sought to identify molecules associated with JEV entry to microglial cells. Virus overlay protein-binding assay (VOPBA) and liquid chromatography-mass spectrometry (LC/MS/MS) identified the 37/67 kDa high-affinity laminin receptor protein and nucleolin as a potential JEV-binding proteins. These proteins were subsequently investigated for a contribution to JEV entry to mouse microglial BV-2 cells together with other possible candidate receptor molecules including Hsp70, Hsp90, GRP78, CD14, and CD4. In antibody mediated inhibition of infection experiments, both anti-laminin receptor and anti-CD4 antibodies significantly reduced virus entry while anti-Hsp70 and 90 antibodies produced a slight reduction. Significant inhibition of virus entry (up to 80%) was observed in the presence of lipopolysaccharide (LPS) which resulted in a complete down-regulation of CD4 and moderate down-regulation of CD14. These results suggest that multiple receptor proteins may mediate the entry of JEV to microglial cells, with CD4 playing a major role.

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“…It has been proposed in recent studies that viral reservoirs, and the release of neurotoxic cytokines and pro-oxidants may mediate microglia-induced neuronal injury following JEV infection (Chen et al, 2010;Ghoshal et al, 2007;Raung et al, 2005;Swarup et al, 2008;Thongtan et al, 2010). Blakely et al (2009) has reported that glutamate excitoneurotoxicity mediates bystander neuronal injury following West Nile virus infection, a member of the family Flaviviridae.…”

Section: Introductionmentioning

confidence: 99%

Glutamate released by Japanese encephalitis virus‐infected microglia involves TNF‐α signaling and contributes to neuronal death

Chen

Chang

et al. 2011

Glia

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The substantial activation of microglia in Japanese encephalitis virus (JEV)-induced Japanese encephalitis found in numerous studies demonstrates that the disease pathogenesis involves bystander damage caused by microglia-released mediators. Previously, we reported that microglia synthesized and secreted bioactive mediators with neurotoxic potential into the cultured supernatants in response to JEV infection. In this study, we found that the supernatants of JEV-infected microglia caused MK801-inhibitable neuronal damage in cultured neurons, indicating a potential excitotoxic mechanism. Infection with JEV was found to elicit the extracellular glutamate accumulation from microglia but not from neuron and astrocyte cultures. The glutaminase inhibitor 6-diazo-5-oxo-L-norleucine, cystine/glutamate antiporter inhibitor α-aminoadipic acid, and the gap junction inhibitor carbenoxolone reduced JEV infection-induced microglial glutamate release and neurotoxicity. We further demonstrated that tumor necrosis factor-alpha (TNF-α) was a key cytokine which stimulated extensive microglial glutamate release by up-regulating glutaminase expression via signals involving protein kinase C, cAMP responsive element-binding protein, and CAAT-enhancer-binding protein-beta. Although the elevated expression of excitatory amino acid transporter 1 and 2 was observed in JEV-infected cells, the glutamate uptake activity was significantly inhibited by TNF-α. The JEV infection-induced alterations, such as the extracellular glutamate release and glutamate-mediated excitoneurotoxicity, also occurred in neuron/glia cultures. Our findings support a potential link between neuroinflammation and the development of excitotoxic neuronal injury in Japanese encephalitis. The link between neuroinflammation and excitotoxic death may involve a mechanism in which TNF-α released by microglia plays a facilitory role in glutamate excitoneurotoxicity via up-regulation of glutamate synthesis and down-regulation of glutamate uptake.

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Highly permissive infection of microglial cells by Japanese encephalitis virus: a possible role as a viral reservoir

Cited by 62 publications

References 27 publications

Immunobiology of Japanese Encephalitis Virus

Immunobiology of Japanese Encephalitis Virus

Characterization of putative Japanese encephalitis virus receptor molecules on microglial cells

Glutamate released by Japanese encephalitis virus‐infected microglia involves TNF‐α signaling and contributes to neuronal death

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