title: Differential Roles of Chemokines CCL2 and CCL7 in Monocytosis and Leukocyte Migration during West Nile Virus Infection.
abstract: West Nile virus (WNV) is a re-emerging pathogen and the leading cause of epidemic encephalitis in the United States. Inflammatory monocytes are a critical component of the cellular infiltrate found in the CNS during WNV encephalitis, although the molecular cues involved in their migration are not fully understood. In mice, we previously showed that WNV infection induces a CCR2-dependent monocytosis that precedes monocyte migration into the CNS. Currently, the relative contribution of the CCR2 ligands, chemokines CCL2 and CCL7, in directing monocyte mobilization and leukocyte migration into the CNS is unclear. In this study, we demonstrate that, although both CCL2 and CCL7 are required for efficient monocytosis and monocyte accumulation in the CNS, only CCL7 deficiency resulted in increased viral burden in the brain and enhanced mortality. The enhanced susceptibility in the absence of CCL7 was associated with the delayed migration of neutrophils and CD8(+) T cells into the CNS compared with WT or Ccl2(-/-) mice. To determine whether CCL7 reconstitution could therapeutically alter the survival outcome of WNV infection, we administered exogenous CCL7 i.v. to WNV-infected Ccl7(-/-) mice and observed a significant increase in monocytes and neutrophils, but not CD8(+) T cells, within the CNS, as well as an enhancement in survival compared with Ccl7(-/-) mice treated with a linear CCL7 control peptide. Our experiments suggest that CCL7 is an important protective signal involved in leukocyte trafficking during WNV infection, and it may have therapeutic potential for the treatment of acute viral infections of the CNS.
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Susana V
authors.initials: SV
authors.lastname: Bardina
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Daniela
authors.initials: D
authors.lastname: Michlmayr
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Hoffman
authors.affiliation: Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Obara
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029;
authors.forename: Janet
authors.initials: J
authors.lastname: Sum
authors.affiliation: Cardiovascular Research Institute, Department of Medicine, University of California San Francisco, San Francisco, CA 94549;
authors.forename: Israel F
authors.initials: IF
authors.lastname: Charo
authors.affiliation: Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201; Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201; and.
authors.forename: Wuyuan
authors.initials: W
authors.lastname: Lu
authors.affiliation: Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Pletnev
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029; jean.lim@mssm.edu.
authors.forename: Jean K
authors.initials: JK
authors.lastname: Lim
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002465:Cell Movement; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism*; D054410:Chemokine CCL7 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D002522:Chlorocebus aethiops; D018792:Encephalitis, Viral / Q000235:genetics / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015870:Gene Expression; D054884:Host-Pathogen Interactions; D007964:Leukocytosis / Q000235:genetics / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014709:Vero Cells; D014901:West Nile Fever / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D014902:West Nile virus / Q000502:physiology
chemical_list: C491768:Ccl2 protein, mouse; C515451:Ccl7 protein, mouse; D018932:Chemokine CCL2; D054410:Chemokine CCL7