Abstract
Chandipura Virus (CHPV), a negative-stranded RNA virus belonging to the Rhabdoviridae family, has been previously reported to bring neuronal apoptosis by activating several factors leading to neurodegeneration. Following virus infection of the central nervous system, microglia, the ontogenetic and functional equivalents of macrophages in somatic tissues gets activated and starts secreting chemokines, thereby recruiting peripheral leukocytes into the brain parenchyma. In the present study, we have systemically examined the effect of CHPV on microglia and the activation of cellular signalling pathways leading to chemokine expression upon CHPV infection. Protein and mRNA expression profiles of chemokine genes revealed that CHPV infection strongly induces the expression of CXC chemokine ligand 10 (CXCL10) and CC chemokine ligand 5 (CCL5) in microglia. CHPV infection triggered the activation of signalling pathways mediated by mitogen-activated protein kinases, including p38, JNK 1 and 2, and nuclear factor κB (NF-kappaB). CHPV-induced expression of CXCL10 and CCL5 was achieved by the activation of p38 and NF-kappaB pathways. Considering the important role of inflammation in neurodegeneration, we have targeted NF-kappaB using a newly synthesised natural product nitrosporeusine analogue and showed incapability of microglial supernatant of inducing apoptosis in neurons after treatment.
Highlights
Microglia, the developmental and functional equivalents of macrophages in somatic tissues [1], exert a central role in a host defence and immune surveillance against infectious agents in the central nervous system (CNS) [2]
In continuation to that our present study systematically examined the mechanism of microglial activation and function of NF-kappaB in CNS inflammation
We have shown that though Chandipura Virus (CHPV) infection is not productive in microglia, it leads to NF-kappaB activation that regulates secretion of cytokines and chemokines
Summary
The developmental and functional equivalents of macrophages in somatic tissues [1], exert a central role in a host defence and immune surveillance against infectious agents in the central nervous system (CNS) [2]. During viral infection activated microglia respond through a highly regulated network of cytokines and chemokines, which subsequently recruits the peripheral leukocytes into the CNS and orchestrate a multicellular immune response against the infectious agent [5]. Chemokines are low molecular- weight and structurally related signalling molecules that are divided into four subfamilies, designated C, CC, CXC, and CX3C chemokine ligands based on the positions of their cysteine residues [6]. These molecules orchestrate efficient trafficking and recirculation of the leukocyte population within the blood vessels, lymph, lymphoid organs, and tissues, a necessary process during host immune surveillance and in acute and chronic inflammatory responses [7],[8]. Increasing evidence suggests that CNS-resident cells secrete various kinds of signalling chemokines upon injury or infection and that attracts peripheral leukocytes, such as lymphocytes, monocytes, transmigrate toward the chemokine gradient, breaching the blood-brain barrier, and gain access to the brain parenchyma [9],[6]
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