title: TRIF, and TRIF-interacting TLRs differentially modulate several adenovirus vector-induced immune responses.
abstract: The use of Adenovirus (Ad)-based vectors has proven to be a useful platform for the development of gene therapy and vaccine protocols. The immunological mechanisms underlying these properties need to be identified and understood to foster safer, more efficacious use of this important gene transfer platform. Our recent studies have confirmed an important role for MyD88 dependent toll-like receptor (TLR) pathways as mediators of these responses. In this study, we confirm that TLR3, TLR4 and TRIF (TIR-domain-containing adapter-inducing interferon-beta) can also have augmentative or inhibitory roles during Ad-induced immune responses. Importantly, our studies revealed that TLR4 acts to suppress several aspects of the Ad-induced innate immune response, a finding not previously reported for this TLR in any model system. In addition, using MyD88 and TRIF double knockout mice, we demonstrate that the MyD88 and TRIF adaptor proteins can play either additive or redundant roles in mediating certain aspects of Ad vector-induced innate and adaptive immune responses. Furthering this complexity, our model system strongly suggests that non-TLR based systems must not only exist, but also have a significant role to play during Ad vector-mediated induction of adaptive immune responses.
authors.affiliation: Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI 48823, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Appledorn
authors.forename: S
authors.initials: S
authors.lastname: Patial
authors.forename: S
authors.initials: S
authors.lastname: Godbehere
authors.forename: N
authors.initials: N
authors.lastname: Parameswaran
authors.forename: A
authors.initials: A
authors.lastname: Amalfitano
mesh_terms: D056704:Adaptive Immunity; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000276:immunology; D000256:Adenoviridae / Q000276:immunology*; D000818:Animals; D003165:Complement System Proteins / Q000276:immunology; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000276:immunology*; D007113:Immunity, Innate; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology; D051196:Toll-Like Receptor 3 / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000276:immunology*; D014161:Transduction, Genetic
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D003165:Complement System Proteins; D053594:Myeloid Differentiation Factor 88; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse; C519703:TLR3 protein, mouse; C493487:Tlr4 protein, mouse