Abstract
BackgroundThe susceptibility of mice and humans to Chandipura virus infection is age-dependent. Upon experimental infection, mice secrete significant amounts of proinflammatory cytokines. Similarly, children who recover from natural infection with the virus show significant amounts of TNF-α production, suggesting that innate immunity plays a major role in the response to Chandipura virus. Toll-like receptors (TLR) are key host molecules involved in innate immune responses in infections. Therefore, the aim of this study was to examine the role of TLR in the response to Chandipura virus infection.MethodsThe mouse monocyte-macrophage cell line, RAW 264.7, and C3H/HeJ mice were used as models. Micro array techniques were used to identify the type of TLR involved in the response to infection. The results were validated by examining TLR expression using flow cytometry and by measuring the levels of proinflammatory cytokines and nitric oxide (NO) in the culture supernatants using bead assays and the Griess method, respectively. The pathogenic role of Toll-like receptor 4 (TLR4) was studied in a TLR4 mutant strain of mice -C3H/HeJ and the results compared with those from wild-type mice- C3H/CaJ. The pathogenic effects of NO were studied by treating experimentally infected mice with the NO inhibitor, aminoguanidine (AG).ResultsThe micro array results showed that TLR4 was regulated after Chandipura virus infection. At high multiplicities of infection (10 MOI), RAW cells up- regulated cell surface expression of TLR4 and secreted significant amounts of TNF-α, MCP-1, IL-10 and IL-12 and NO. The survival rate of C3H/HeJ mice was higher than those of wild-type C3H/CaJ mice. The survived C3H/HeJ mice secreted significant quantity of MCP-1 and IFN-γ cytokines and cleared virus from brain. Similarly, the survival rate of AG-treated mice was higher than those of the untreated controls.ConclusionsChandipura virus regulates TLR4, which leads to the secretion of proinflammatory cytokines and NO by infected RAW cells. Difference in survival rate in TLR4 mutant mice and nitric oxide inhibitor treated mice, confirmed the role of these molecules in disease pathogenesis. The result is significant in clinical management and designing antiviral intervention for Chandipura virus infection.
Highlights
The susceptibility of mice and humans to Chandipura virus infection is age-dependent
We focused on the types of Toll-like receptors (TLR) involved in immune responses to Chandipura virus (CHPV) infection using RAW cells as an in vitro model
Toll-like receptor 4 (TLR4) in disease pathogenesis To explore the possibility that TLR4 is involved in disease pathogenesis, wild-type C3H/CaJ mice and TLR4 mutant C3H/HeJ mice were infected with CHPV
Summary
The susceptibility of mice and humans to Chandipura virus infection is age-dependent. Children who recover from natural infection with the virus show significant amounts of TNF-α production, suggesting that innate immunity plays a major role in the response to Chandipura virus. Susceptibility studies in mice show that CHPV is lethal to young mice, but adults are only susceptible through the intra-cerebral route of infection [3] This age-dependent susceptibility is apparent in nude mice [4]. Virus-infected young mice secrete significant amounts of proinflammatory cytokines [5] and children who have recovered from natural infections secrete significant levels of TNF-α [6] Taken, together, these observations strongly suggest that innate immunity plays a pivotal role in protection from CHPV infection. The role of innate immunity is critical during early childhood, when humoral and cell mediated immune responses are not fully developed
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