title: Targeted blockade in lethal West Nile virus encephalitis indicates a crucial role for very late antigen (VLA)-4-dependent recruitment of nitric oxide-producing macrophages.
abstract: Infiltration of Ly6C(hi) monocytes from the blood is a hallmark of viral encephalitis. In mice with lethal encephalitis caused by West Nile virus (WNV), an emerging neurotropic flavivirus, inhibition of Ly6C(hi) monocyte trafficking into the brain by anti-very late antigen (VLA)-4 integrin antibody blockade at the time of first weight loss and leukocyte influx resulted in long-term survival of up to 60% of infected mice, with subsequent sterilizing immunity. This treatment had no effect on viral titers but appeared to be due to inhibition of Ly6C(hi) macrophage immigration. Although macrophages isolated from the infected brain induced WNV-specific CD4(+) T-cell proliferation, T cells did not directly contribute to pathology, but are likely to be important in viral control, as antibody-mediated T-cell depletion could not reproduce the therapeutic benefit of anti-VLA-4. Instead, 70% of infiltrating inflammatory monocyte-derived macrophages were found to be making nitric oxide (NO). Furthermore, aminoguanidine-mediated inhibition of induced NO synthase activity in infiltrating macrophages significantly prolonged survival, indicating involvement of NO in the immunopathology. These data show for the first time the therapeutic effects of temporally targeting pathogenic NO-producing macrophages during neurotropic viral encephalitis.
authors.affiliation: Discipline of Pathology, School of Medical Sciences Faculty of Medicine, The University of Sydney, Blackburn Building D06, Sydney, NSW 2006, Australia.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Getts
authors.forename: Rachael L
authors.initials: RL
authors.lastname: Terry
authors.forename: Meghann Teague
authors.initials: MT
authors.lastname: Getts
authors.forename: Marcus
authors.initials: M
authors.lastname: Müller
authors.forename: Sabita
authors.initials: S
authors.lastname: Rana
authors.forename: Celine
authors.initials: C
authors.lastname: Deffrasnes
authors.forename: Thomas Myles
authors.initials: TM
authors.lastname: Ashhurst
authors.forename: Jane
authors.initials: J
authors.lastname: Radford
authors.forename: Markus
authors.initials: M
authors.lastname: Hofer
authors.forename: Shane
authors.initials: S
authors.lastname: Thomas
authors.forename: Iain L
authors.initials: IL
authors.lastname: Campbell
authors.forename: Nicholas J C
authors.initials: NJ
authors.lastname: King
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001921:Brain / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015967:Gene Expression Regulation, Viral / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D039041:Integrin alpha4beta1 / Q000276:immunology* / Q000378:metabolism*; D016023:Integrins / Q000235:genetics / Q000378:metabolism; D016169:Lymphocyte Function-Associated Antigen-1 / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism* / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration / Q000276:immunology; D052247:Nitric Oxide Synthase Type II; D014901:West Nile Fever / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D015703:Antigens, CD; D015815:Cell Adhesion Molecules; D005904:Glial Fibrillary Acidic Protein; D039041:Integrin alpha4beta1; D016023:Integrins; D016169:Lymphocyte Function-Associated Antigen-1; D052247:Nitric Oxide Synthase Type II