title: Both Cerebral and Hematopoietic Deficiencies in CCR2 Result in Uncontrolled Herpes Simplex Virus Infection of the Central Nervous System in Mice.
abstract: CCR2 is a chemokine receptor expressed on the surface of blood leukocytes, particularly «Ly6Chi» inflammatory monocytes and microglia. Signaling through this receptor is thought to influence the immune activity of microglia as well as monocytes egress from the bone marrow (BM) and their trafficking into the central nervous system (CNS) in several neurological diseases. During experimental herpes simplex virus 1 (HSV-1) encephalitis (HSE), CCR2 deficiency has been reported to exacerbate the outcome of the disease. However, the precise contribution of CCR2 expressed in cells of the CNS or peripheral monocytes in the protection against HSE remains unclear. To dissect the differential role of CCR2 during HSE, chimeric mice with receptor deficiency in the brain or blood cells were generated by transplanting wild-type (WT) C57BL/6 or CCR2-/- BM-derived cells in CCR2-/- (WT→CCR2-/-) and WT (CCR2-/-→WT) mice, respectively. Our results indicate that following intranasal infection with 1.2x106 plaque forming units of HSV-1, CCR2 deficiency in hematopoietic cells and, to a lesser extent, in CNS exacerbates the outcome of HSE. Mortality rates of CCR2-/- (71.4%) and CCR2-/-→WT (57.1%) mice were significantly higher than that of WT (15.3%; P<0.01 and P<0.05, respectively) but the difference did not reach statistical significance for WT→CCR2-/- animals (42.8%; P = 0.16). Both peripheral and CNS deficiencies in CCR2 resulted in increased infectious viral titers and wider dissemination of HSV antigens in the brain as well as an overproduction of inflammatory cytokines and chemokines including IL-1β, IL-6, CCL2, CCL3 and CCL5. Furthermore, CCR2 deficiency in the hematopoietic system altered monocytes egress from the BM and their recruitment to the CNS, which may contribute to the failure in HSV-1 containment. Collectively, these data suggest that CCR2 expressed on cells of CNS and especially on peripheral monocytes is important for the control of HSV-1 replication and inflammatory environment during experimental HSE.
authors.affiliation: Research Center in Infectious Diseases, CHU of Quebec Research Center, Department of microbiology-immunology and infectious diseases, Faculty of Medicine, Laval University, Quebec City, QC, Canada.
authors.forename: Rafik
authors.initials: R
authors.lastname: Menasria
authors.affiliation: Research Center in Infectious Diseases, CHU of Quebec Research Center, Department of microbiology-immunology and infectious diseases, Faculty of Medicine, Laval University, Quebec City, QC, Canada.
authors.forename: Coraline
authors.initials: C
authors.lastname: Canivet
authors.affiliation: Research Center in Infectious Diseases, CHU of Quebec Research Center, Department of microbiology-immunology and infectious diseases, Faculty of Medicine, Laval University, Quebec City, QC, Canada.
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Piret
authors.affiliation: Laboratory of Innate Immunity, CHU of Quebec Research Center, Department of Molecular Medicine, Faculty of Medicine, Laval University, Quebec City, QC, Canada.
authors.forename: Jean
authors.initials: J
authors.lastname: Gosselin
authors.affiliation: Research Center in Infectious Diseases, CHU of Quebec Research Center, Department of microbiology-immunology and infectious diseases, Faculty of Medicine, Laval University, Quebec City, QC, Canada.
authors.forename: Guy
authors.initials: G
authors.lastname: Boivin
mesh_terms: D000818:Animals; D001921:Brain / Q000276:immunology*; D001923:Brain Chemistry / Q000276:immunology; D020803:Encephalitis, Herpes Simplex / Q000276:immunology*; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000276:immunology*; D018259:Herpesvirus 1, Human / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000276:immunology / Q000378:metabolism; D009000:Monocytes / Q000276:immunology; D054390:Receptors, CCR2 / Q000172:deficiency* / Q000502:physiology; D019562:Viral Load / Q000276:immunology
chemical_list: C515335:Ccr2 protein, mouse; D054390:Receptors, CCR2