Neuronal CXCL10 Directs CD8<sup>+</sup>T-Cell Recruitment and Control of West Nile Virus Encephalitis

Klein, Robyn S.; Lin, Eugene C.; Zhang, Bo; Luster, Andrew D.; Tollett, Judy; Samuel, Melanie A.; Engle, Michael J.; Diamond, Michael S.

doi:10.1128/jvi.79.17.11457-11466.2005

Cited by 388 publications

(485 citation statements)

References 61 publications

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“…These cultures were of high purity (Ͼ90% for the neuronal marker MAP-2) and exquisitely sensitive to WNV infection (20); costaining experiments confirmed that WNV infection localized to neurons (Fig. 4A).…”

Section: Wnv Infection Of Primary Neurons Induces Caspase 3 Activationmentioning

confidence: 76%

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Caspase 3-Dependent Cell Death of Neurons Contributes to the Pathogenesis of West Nile Virus Encephalitis

Samuel¹,

Morrey

Diamond

2007

J Virol

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162

176

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West Nile virus (WNV) is a neurotropic, arthropod-borne flavivirus that has become a significant global cause of viral encephalitis. To examine the mechanisms of WNV-induced neuronal death and the importance of apoptosis in pathogenesis, we evaluated the role of a key apoptotic regulator, caspase 3. WNV infection induced caspase 3 activation and apoptosis in the brains of wild-type mice. Notably, congenic caspase 3 ؊/؊ mice were more resistant to lethal WNV infection, although there were no significant differences in the tissue viral burdens or the kinetics of viral spread. Instead, decreased neuronal death was observed in the cerebral cortices, brain stems, and cerebella of caspase 3 ؊/؊ mice. Analogously, primary central nervous system (CNS)-derived neurons demonstrated caspase 3 activation and apoptosis after WNV infection, and treatment with caspase inhibitors or a genetic deficiency in caspase 3 significantly decreased virus-induced death. These studies establish that caspase 3-dependent apoptosis contributes to the pathogenesis of lethal WNV encephalitis and suggest possible novel therapeutic targets to restrict CNS injury.

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Section: Wnv Infection Of Primary Neurons Induces Caspase 3 Activationmentioning

confidence: 76%

“…Cortical neurons were prepared from embryonic day 15 wild-type and congenic caspase 3 Ϫ/Ϫ mouse embryos essentially as previously described (20). The cells were seeded in 24-well poly-D-lysine/laminin-coated plates at a density of 5 ϫ 10 5 cells/well in Dulbecco's modified Eagle's medium containing 5% HI FBS and 5% horse serum.…”

Section: Methodsmentioning

confidence: 99%

Caspase 3-Dependent Cell Death of Neurons Contributes to the Pathogenesis of West Nile Virus Encephalitis

Samuel¹,

Morrey

Diamond

2007

J Virol

Self Cite

162

176

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“…CCL3-CCL5, chemokines that all bind the chemokine receptor CCR5, are strongly induced in the CNS after WNV infection (43)(44)(45)(46), and targeted deletion of CCR5 is associated with depressed leukocyte trafficking, increased viral burden, and enhanced mortality (43). WNV encephalitis is associated with the early expression of CXCL10 by virally infected neurons that proceeds in a caudal-torostral direction within the CNS with significantly higher levels detected in the cerebellum by day 5 postinfection (44). Loss of CXCL10 was associated with decreased recruitment of WNV-specific CD8 T cells into the CNS, high CNS viral loads, and enhanced mortality.…”

Section: T He Infiltration Of Virus-specific Cd8 T Cells Is Essentialmentioning

confidence: 99%

CXCR3 Mediates Region-Specific Antiviral T Cell Trafficking within the Central Nervous System during West Nile Virus Encephalitis

Zhang

Chan

Liu

et al. 2008

The Journal of Immunology

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163

147

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Regional differences in inflammation during viral infections of the CNS suggest viruses differentially induce patterns of chemoattractant expression, depending on their cellular targets. Previous studies have shown that expression of the chemokine CXCL10 by West Nile virus (WNV)-infected neurons is essential for the recruitment of CD8 T cells for the purpose of viral clearance within the CNS. In the current study we used mice deficient for the CXCL10 receptor, CXCR3, to evaluate its role in leukocyte-mediated viral clearance of WNV infection within various CNS compartments. WNV-infected CXCR3-deficient mice exhibited significantly enhanced mortality compared with wild-type controls. Immunologic and virologic analyses revealed that CXCR3 was dispensable for control of viral infection in the periphery and in most CNS compartments but, surprisingly, was required for CD8 T cell-mediated antiviral responses specifically within the cerebellum. WNV-specific, CXCR3-expressing T cells preferentially migrated into the cerebellum, and WNV-infected cerebellar granule cell neurons expressed higher levels of CXCL10 compared with similarly infected cortical neurons. These results indicate that WNV differentially induces CXCL10 within neuronal populations and suggest a novel model for nonredundancy in chemokine-mediated inflammation among CNS compartments.

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“…All experiments with HBMVECs and HBCAs were performed on cells passaged no more than 14 times. Primary cortical neurons were prepared from day 15 C57BL/6 mouse embryos as previously described (17,18). Cortical neuron experiments were performed using neurons that were cultured for 3 to 4 days in neurobasal medium containing B27 and L-glutamine (Invitrogen).…”

Section: Cells and Virusesmentioning

confidence: 99%

Differential Replication of Pathogenic and Nonpathogenic Strains of West Nile Virus within Astrocytes

Hussmann

Samuel

Kim

et al. 2013

J Virol

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The severity of West Nile virus (WNV) infection in immunocompetent animals is highly strain dependent, ranging from avirulent to highly neuropathogenic. Here, we investigate the nature of this strain-specific restriction by analyzing the replication of avirulent (WNV-MAD78) and highly virulent (WNV-NY) strains in neurons, astrocytes, and microvascular endothelial cells, which comprise the neurovascular unit within the central nervous system (CNS). We demonstrate that WNV-MAD78 replicated in and traversed brain microvascular endothelial cells as efficiently as WNV-NY. Likewise, similar levels of replication were detected in neurons. Thus, WNV-MAD78's nonneuropathogenic phenotype is not due to an intrinsic inability to replicate in key target cells within the CNS. In contrast, replication of WNV-MAD78 was delayed and reduced compared to that of WNV-NY in astrocytes. The reduced susceptibility of astrocytes to WNV-MAD78 was due to a delay in viral genome replication and an interferon-independent reduction in cell-to-cell spread. Together, our data suggest that astrocytes regulate WNV spread within the CNS and therefore are an attractive target for ameliorating WNV-induced neuropathology.

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Neuronal CXCL10 Directs CD8⁺T-Cell Recruitment and Control of West Nile Virus Encephalitis

Cited by 388 publications

References 61 publications

Caspase 3-Dependent Cell Death of Neurons Contributes to the Pathogenesis of West Nile Virus Encephalitis

Caspase 3-Dependent Cell Death of Neurons Contributes to the Pathogenesis of West Nile Virus Encephalitis

CXCR3 Mediates Region-Specific Antiviral T Cell Trafficking within the Central Nervous System during West Nile Virus Encephalitis

Differential Replication of Pathogenic and Nonpathogenic Strains of West Nile Virus within Astrocytes

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Neuronal CXCL10 Directs CD8+T-Cell Recruitment and Control of West Nile Virus Encephalitis

Cited by 388 publications

References 61 publications

Caspase 3-Dependent Cell Death of Neurons Contributes to the Pathogenesis of West Nile Virus Encephalitis

Caspase 3-Dependent Cell Death of Neurons Contributes to the Pathogenesis of West Nile Virus Encephalitis

CXCR3 Mediates Region-Specific Antiviral T Cell Trafficking within the Central Nervous System during West Nile Virus Encephalitis

Differential Replication of Pathogenic and Nonpathogenic Strains of West Nile Virus within Astrocytes

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Neuronal CXCL10 Directs CD8⁺T-Cell Recruitment and Control of West Nile Virus Encephalitis