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Open Access Short report

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

Daniel R Getts13, Rachael L Terry13, Meghann Teague Getts13, Marcus Müller23, Sabita Rana13, Celine Deffrasnes13, Thomas Myles Ashhurst13, Jane Radford13, Markus Hofer23, Shane Thomas4, Iain L Campbell23 and Nicholas JC King13*

Author Affiliations

1 The Discipline of Pathology, School of Medical Sciences Faculty of Medicine, The University of Sydney, Blackburn Building D06, Sydney, NSW 2006, Australia

2 The School of Molecular Biosciences, Faculty of Science, University of Sydney, Sydney, Australia

3 The Bosch Institute, University of Sydney, Sydney, Australia

4 The Centre for Vascular Research, School of Medical Sciences, University of New South Wales, Sydney, Australia

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Journal of Neuroinflammation 2012, 9:246  doi:10.1186/1742-2094-9-246

Published: 30 October 2012

Abstract

Infiltration of Ly6Chi 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 Ly6Chi 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 Ly6Chi 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.

Keywords:
Neurotropic virus; Flavivirus; Inflammatory monocytes; West Nile virus encephalitis; Macrophage infiltration; VLA-4; Integrins; Nitric oxide