title: Chemokine Receptor Ccr7 Restricts Fatal West Nile Virus Encephalitis.
abstract: West Nile virus (WNV) is a mosquito-transmitted flavivirus that can cause debilitating encephalitis. To delineate the mechanisms behind this pathology, we studied Ccr7-deficient mice, which afforded us the capacity to study infection in mice with disrupted peripheral cellular trafficking events. The loss of Ccr7 resulted in an immediate pan-leukocytosis that remained elevated throughout the infection. This leukocytosis resulted in a significant enhancement of leukocyte accumulation within the central nervous system (CNS). Despite an excess of virus-specific T cells in the CNS, Ccr7-deficient mice had significantly higher CNS viral loads and mortality rates than wild-type animals. Mechanistically, the elevated trafficking of infected myeloid cells into the brain in Ccr7-deficient mice resulted in increased levels of WNV in the CNS, thereby effectively contributing to neuroinflammation and lowering viral clearance. Combined, our experiments suggest that during WNV infection, Ccr7 is a gatekeeper for nonspecific viral transference to the brain.IMPORTANCEIn this study, we show that Ccr7 is required for the sufficient migration of dendritic cells and T cells into the draining lymph node immediately following infection and for the restriction of leukocyte migration into the brain. Further, the severe loss of dendritic cells in the draining lymph node had no impact on viral replication in this organ, suggesting that WNV may migrate from the skin into the lymph node through another mechanism. Most importantly, we found that the loss of Ccr7 results in a significant leukocytosis, leading to hypercellularity within the CNS, where monocytes/macrophages contribute to CNS viremia, neuroinflammation, and increased mortality. Together, our data point to Ccr7 as a critical host defense restriction factor limiting neuroinflammation during acute viral infection.
authors.affiliation: The Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Susana V
authors.initials: SV
authors.lastname: Bardina
authors.affiliation: The Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Julia A
authors.initials: JA
authors.lastname: Brown
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Daniela
authors.initials: D
authors.lastname: Michlmayr
authors.affiliation: The Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.|Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Hoffman
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Janet
authors.initials: J
authors.lastname: Sum
authors.affiliation: Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Pletnev
authors.affiliation: Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Sergio A
authors.initials: SA
authors.lastname: Lira
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York, USA jean.lim@mssm.edu.
authors.forename: Jean K
authors.initials: JK
authors.lastname: Lim
mesh_terms: D000818:Animals; D001921:Brain / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000473:pathology; D002490:Central Nervous System / Q000276:immunology / Q000821:virology; D003713:Dendritic Cells / Q000473:pathology; D054884:Host-Pathogen Interactions; D007964:Leukocytosis / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054400:Receptors, CCR7 / Q000172:deficiency / Q000276:immunology*; D019562:Viral Load; D014901:West Nile Fever / Q000276:immunology* / Q000821:virology*; D014902:West Nile virus / Q000472:pathogenicity* / Q000502:physiology
chemical_list: D054400:Receptors, CCR7
keywords: arbovirus; cell trafficking; chemokine receptors; chemokines; host-pathogen interactions; leukocytes; neuroimmunology; viral pathogenesis