Abstract
Neurotropic viruses induce neurodegeneration either directly by activating host death domains or indirectly through host immune response pathways. Chandipura Virus (CHPV) belonging to family Rhabdoviridae is ranked among the emerging pathogens of the Indian subcontinent. Previously we have reported that CHPV induces neurodegeneration albeit the root cause of this degeneration is still an open question. In this study we explored the role of microglia following CHPV infection. Phenotypic analysis of microglia through lectin and Iba-1 staining indicated cells were in an activated state post CHPV infection in cortical region of the infected mouse brain. Cytokine Bead Array (CBA) analysis revealed comparatively higher cytokine and chemokine levels in the same region. Increased level of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), Nitric Oxide (NO) and Reactive Oxygen species (ROS) in CHPV infected mouse brain indicated a strong inflammatory response to CHPV infection. Hence it was hypothesized through our analyses that this inflammatory response may stimulate the neuronal death following CHPV infection. In order to validate our hypothesis supernatant from CHPV infected microglial culture was used to infect neuronal cell line and primary neurons. This study confirmed the bystander killing of neurons due to activation of microglia post CHPV infection.
Highlights
Inflammation as reported previously is a “double edged sword” for CNS1
In this report we have explored the phenomenon of microglial activation pattern due to Chandipura Virus (CHPV) infection and measured the amount of pro-inflammatory cytokines secreted in different regions of the mouse brain post infection
Mouse brain sections from cortex, hippocampus, thalamus and striatum were stained with Nissl for analysing the neuronal population post CHPV infection
Summary
Evaluation of neurodegeneration in various brain regions post CHPV infection. Mouse brain sections from cortex, hippocampus, thalamus and striatum were stained with Nissl for analysing the neuronal population post CHPV infection. A time dependent analysis of microglial activation was observed by Iba-1 staining in vivo that showed an increasing number of activated microglia post CHPV infection (Fig. S1 A,B). Neuronal cells treated with supernatant obtained from CHPV infected microglia showed significantly higher number of TUNEL positive cells compared to mock infected cells (Fig. 6A). TUNEL positive cells were significantly higher compared to mock infected cells (Fig. 6B) These analyses indicated that microglial supernatant contained pro-inflammatory mediators that had lethal effect on neurons. Cells were incubated with serum-free medium for 4 hour before treating with UV inactivated supernatant of
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