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

Abstract

BackgroundDengue, 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.MethodsC57BL/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.ResultsAll 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.ConclusionIntracerebral infection with non-adapted DENV-3 induces encephalitis and behavioral changes that precede lethality in mice.

Neurological sequelae induced by alphavirus infection of the CNS are attenuated by treatment with the glutamine antagonist 6-diazo-5-oxo-l-norleucine

“…Although virus-induced behavioral alterations in mice have been previously reported (Amaral et al 2011; Jurgens et al 2012; Umpierre et al 2014), to our knowledge, this is the first study of cognitive deficits and other behavioral abnormalities in a mouse model of alphavirus infection. The continued emergence of viral encephalomyelitis outbreaks around the world emphasizes the need to identify novel therapeutics to improve outcome using an animal model.…”

Platelet Activating Factor (PAF) Receptor Deletion or Antagonism Attenuates Severe HSV-1 Meningoencephalitis

“…All analysed sections had areas of cerebrum, brainstem, hippocampus and cerebellum. Meningeal inflammation was assessed and graded as follows: 0 = no inflammation; 1 = one cell layer of inflammation; 2 = two cell layers of inflammation; 3 = three cell layers of inflammation; 4 = four or more cell layers of inflammation (Amaral et al 2011). The perivascular cuffing was quantitatively classified as: (−) no significant lesions, (+) mild, (++) moderate and (+++) intense changes (Vilela et al 2008).…”

Flaviviruses, an expanding threat in public health: focus on dengue, West Nile, and Japanese encephalitis virus

“…CCL2, CCL5, CXCL1, and CXCL2) and inflammatory cytokines (e.g. TNF-α and IFN-γ) that facilitate leukocyte infiltration into the CNS (Amaral et al , 2011a; Amaral et al , 2011b). …”

“…Mice infected intracerebrally with DENV-3 show progressive meningo-encephalitis characterized by CNS infiltration of neutrophils and mononuclear cells by a mechanism that correlates with a chemokine-dependent mechanism that includes CCL2 and CXCL12 (Amaral et al , 2011a; Amaral et al , 2011b). These results show the importance of these cell types in the development of CNS disease during DENV infection.…”