title: Enhanced viral clearance and reduced leukocyte infiltration in experimental herpes encephalitis after intranasal infection of CXCR3-deficient mice.
abstract: Herpes simplex virus type 1 (HSV-1) encephalitis (HSE) is the most common fatal sporadic encephalitis in developed countries. There is evidence from HSE animal models that not only direct virus-mediated damage caused but also the host's immune response contributes to the high mortality of the disease. Chemokines modulate and orchestrate this immune response. Previous experimental studies in HSE models identified the chemokine receptor CXCR3 and its ligands as molecules with a high impact on the course of HSE in mouse models. In this study, the role of the chemokine receptor CXCR3 was evaluated after intranasal infection with the encephalitogenic HSV-1 strain 17 syn+using CXCR3-deficient mice (CXCR3-/-) and wild-type controls. We demonstrated a neurotropic viral spread into the CNS of after intranasal infection. Although viral load and histological distribution of infected neurons were independent from CXCR3 signaling early after infection, CXCR3-deficient mice cleared HSV-1 more efficiently 14 days after infection. Furthermore, CXCR3 deficiency led to a decreased weight loss in mice after HSV-1 infection. T cell infiltration and microglial activation was prominently reduced by inhibition of CXCR3 signaling. Quantitative PCR of proinflammatory cytokines and chemokines confirmed the reduced neuroinflammatory response in CXCR3-deficient mice during HSE. Our results demonstrate that the recruitment of peripheral immune cells into the CNS, induction of neuroinflammation, and consecutive weight loss during herpes encephalitis is modulated by CXCR3 signaling. Interruption of the CXCR3 pathway ameliorates the detrimental host immune response and in turn, leads paradoxically to an enhanced viral clearance after intranasal infection. Our data gives further insight into the role of CXCR3 during HSE after intranasal infection.
authors.affiliation: Department of Neurology, Universitätsklinikum Bonn, Sigmund-Freud-Str. 25, 53105, Bonn, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Zimmermann
authors.affiliation: University Hospital Münster, Institute of Medical Microbiology-Clinical Virology, Münster, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Hafezi
authors.affiliation: Department of Neurology, Universitätsklinikum Bonn, Sigmund-Freud-Str. 25, 53105, Bonn, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Dockhorn
authors.affiliation: University Hospital Münster, Institute of Medical Microbiology-Clinical Virology, Münster, Germany.
authors.forename: Eva U
authors.initials: EU
authors.lastname: Lorentzen
authors.affiliation: Department of Neurology, Universitätsklinikum Bonn, Sigmund-Freud-Str. 25, 53105, Bonn, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Krauthausen
authors.affiliation: Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.|Cour Pharmaceutical Development Company, Elmhurst, IL, USA.|The Discipline of Pathology, School of Medical Sciences, The University of Sydney, Sydney, NSW, 2006, Australia.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Getts
authors.affiliation: Department of Neurology, Universitätsklinikum Bonn, Sigmund-Freud-Str. 25, 53105, Bonn, Germany. marcus_mathias_mueller@ukb.uni-bonn.de.
authors.forename: M
authors.initials: M
authors.lastname: Müller
authors.affiliation: University Hospital Münster, Institute of Medical Microbiology-Clinical Virology, Münster, Germany.
authors.forename: Joachim E
authors.initials: JE
authors.lastname: Kühn
authors.affiliation: The Discipline of Pathology, School of Medical Sciences, The University of Sydney, Sydney, NSW, 2006, Australia.
authors.forename: Nicholas J C
authors.initials: NJC
authors.lastname: King
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D001921:Brain / Q000276:immunology* / Q000821:virology; D002465:Cell Movement; D054357:Chemokine CXCL10 / Q000235:genetics / Q000276:immunology; D004279:DNA, Viral / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D060467:Disease Resistance / Q000235:genetics*; D020803:Encephalitis, Herpes Simplex / Q000276:immunology* / Q000473:pathology / Q000821:virology; D005786:Gene Expression Regulation; D018259:Herpesvirus 1, Human / Q000254:growth & development / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D007962:Leukocytes / Q000276:immunology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000276:immunology / Q000821:virology; D054367:Receptors, CXCR3 / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology; D019562:Viral Load; D015431:Weight Loss / Q000276:immunology
chemical_list: D054357:Chemokine CXCL10; C485433:Cxcl10 protein, mouse; C515188:Cxcr3 protein, mouse; D004279:DNA, Viral; D054367:Receptors, CXCR3; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma
keywords: CXCR3; HSV-1; Herpes simplex encephalitis; Intranasal infection route