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Open Access Highly Accessed Research

Intracerebral infection with dengue-3 virus induces meningoencephalitis and behavioral changes that precede lethality in mice

Debora CG Amaral1, Milene A Rachid1, Marcia C Vilela1, Roberta DL Campos1, Gustavo P Ferreira2, David H Rodrigues1, Norinne Lacerda-Queiroz1, Aline S Miranda1, Vivian V Costa1, Marco A Campos3, Erna G Kroon2, Mauro M Teixeira1 and Antonio L Teixeira1*

Author Affiliations

1 Laboratório de Imunofarmacologia, Departamento de Bioquímica e Imunologia, Instituto de Ciências Biológicas (ICB), UFMG, Belo Horizonte, Brazil

2 Laboratório de Vírus, Departamento de Microbiologia, Instituto de Ciências Biológicas (ICB), UFMG, Belo Horizonte, Brazil

3 Centro de Pesquisas René Rachou, Belo Horizonte, Brazil

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Journal of Neuroinflammation 2011, 8:23  doi:10.1186/1742-2094-8-23

Published: 9 March 2011

Abstract

Background

Dengue, one of the most important arboviral diseases of humans, may cause severe systemic disease. Although dengue virus (DENV) has been considered to be a non-neurotropic virus, dengue infection has been associated recently with a series of neurological syndromes, including encephalitis. In this work, we evaluated behavioral changes and inflammatory parameters in C57BL/6 mice infected with non-adapted dengue virus 3 (DENV-3) genotype I.

Methods

C57BL/6 mice received 4 × 103 PFU of DENV-3 by an intracranial route. We evaluated the trafficking of leukocytes in brain microvasculature using intravital microscopy, and evaluated chemokine and cytokine profiling by an ELISA test at 3 and 6 days post infection (p.i.). Furthermore, we determined myeloperoxidase activity and immune cell populations, and also performed histopathological analysis and immunostaining for the virus in brain tissue.

Results

All animals developed signs of encephalitis and died by day 8 p.i. Motor behavior and muscle tone and strength parameters declined at day 7 p.i. We observed increased leukocyte rolling and adhesion in brain microvasculature of infected mice at days 3 and 6 p.i. The infection was followed by significant increases in IFN-γ, TNF-α, CCL2, CCL5, CXCL1, and CXCL2. Histological analysis showed evidence of meningoencephalitis and reactive gliosis. Increased numbers of neutrophils, CD4+ and CD8+ T cells were detected in brain of infected animals, notably at day 6 p.i. Cells immunoreactive for anti-NS-3 were visualized throughout the brain.

Conclusion

Intracerebral infection with non-adapted DENV-3 induces encephalitis and behavioral changes that precede lethality in mice.