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Title: Activation of TLR7-Dependent Signaling Pathway in Response to Enterovirus Infection
Authors: Marwa I.A. Alkhabbaz 
Supervisor: Dr. Wassim Chehadeh
Keywords: TLR7;enteroviruses;antiviral activity;cytokines;MxA;inflammation
Issue Date: 2011
Publisher:  Kuwait university - college of graduate studies
Abstract: Enteroviruses (EVs) are single stranded RNA viruses consisting of more than 60 distinct serotypes associated with many serious diseases. The exact mechanism by which an EV is able to evade innate immunity and cause tissue damage still remains unknown. In particular, TLR7 mediates the activation of type I interferon genes and the development of inflammatory cytokine response. The presence of specific EV strains that can strongly activate or inhibit TLR7-dependent signaling pathway was not yet investigated. Hence, the main aim of the study was to explore the antiviral activity and the pattern of cytokine expression in human embryonic kidney cells (HEK293 cells) expressing TLR7 protein following challenge with EVs. TLR7- and mock-transfected HEK293 cells were infected with different types of laboratory EVs (CVB1-5, E7 and E9), and 2 clinical EV isolates (CVB1 and CVB5). The levels of cytokines detected in the supernatants of culture of TLR7-transfected HEK293 cells were higher than those in the supernatants of culture of mock-transfected HEK293 cells following challenge with different types of EVs. CVB4 was shown to induce the production of high levels of IL-6, IL-8 and type I IFNs, whereas very low levels of these cytokines were detected following challenge with CVB2. The clinical CVB1 isolate was more effective activator of TLR7-induced cytokine production than the laboratory CVB1 strain. In comparison to the EV RNA levels in mock-transfected HEK293 cells, a reduced virus replication rate was observed in TLR7-transfected HEK293 cells. A dramatic cytopathic effect (CPE) was observed in mock- and TLR7-transfected HEK293 cells infected with CVB4, E7, E9 or CVB1 isolate. This CPE was not associated with high viral load, but with high levels of IL-6, IL-8 and TNF-. Using the TLR7 expression approach, our results suggest a clear segregation of EVs on the basis of their cytokine induction ability, which may lead to a suppression of EV-induced CPE by antiviral cytokines or an enhancement of the CPE by the proinflammatory cytokines.
Appears in Programs:0520 Microbiology (M.Sc.)

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