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PMID: 18678898 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

CXCR4 antagonism increases T cell trafficking in the central nervous system and improves survival from West Nile virus encephalitis.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 105 ·No. 32 ·2008-08-12 ·Pages 11270-5

McCandless EE, Zhang B, Diamond MS, Klein RS

Abstract

The migration of lymphocytes into the CNS during viral encephalitis is hindered by the blood-brain barrier (BBB) such that most infiltrating cells remain localized to perivascular spaces. This sequestration of leukocytes away from the parenchyma is believed to protect the CNS from immunopathologic injury. Infections of the CNS with highly cytopathic neurotropic viruses, such as West Nile virus (WNV), however, require the parenchymal penetration of T lymphocytes for virus clearance and survival, suggesting that perivascular localization might hinder antiviral immune responses during WNV encephalitis. Using human and murine brain specimens from individuals with WNV encephalitis, we evaluated the expression of CXCL12 and its receptor, CXCR4, at the BBB and tested the hypothesis that inhibition of CXCR4 would promote T lymphocyte entry into the CNS parenchyma and increase viral clearance. Antagonism of CXCR4 significantly improved survival from lethal infection through enhanced intraparenchymal migration of WNV-specific CD8(+) T cells within the brain, leading to reduced viral loads and, surprisingly, decreased immunopathology at this site. The benefits of enhanced CD8(+) T cell infiltration suggest that pharmacologic targeting of CXCR4 may have therapeutic utility for the treatment of acute viral infections of the CNS.

MeSH Terms
Acute Disease Animals Anti-HIV Agents/pharmacology Benzylamines Blood-Brain Barrier/immunology,virology CD8-Positive T-Lymphocytes/immunology Cell Movement/drug effects,immunology Chemokine CXCL12/immunology Cyclams Disease Models, Animal Heterocyclic Compounds/pharmacology Humans Male Mice Receptors, CXCR4/antagonists & inhibitors,immunology West Nile Fever/drug therapy,immunology,virology West Nile virus/immunology
Chemicals
Anti-HIV Agents Benzylamines CXCR4 protein, mouse Chemokine CXCL12 Cxcl12 protein, mouse Cyclams Heterocyclic Compounds Receptors, CXCR4 plerixafor
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
McCandless Erin E
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Zhang Bo
Diamond Michael S
Klein Robyn S
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
1091-6490
DOI
10.1073/pnas.0800898105
Published
2008-08-12
Epub
2008-00-04
Pages
11270-5
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC2495012
Subset
IM
Grants
NINDS NIH HHS · K02 NS045607 · United States
NINDS NIH HHS · R01 NS052632 · United States
NINDS NIH HHS · NS052632 · United States
NINDS NIH HHS · NS045607 · United States
External Links
PubMed source DOI: 10.1073/pnas.0800898105 PMC Full Text View journal details
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