The adjuvant activity of alphavirus replicons is enhanced by incorporating the microbial molecule flagellin into the replicon.Reportar como inadecuado

The adjuvant activity of alphavirus replicons is enhanced by incorporating the microbial molecule flagellin into the replicon. - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

* Corresponding author 1 Department of Microbiology, Tumor and Cell Biology 2 Unit of Immunization 3 Department of Medicine 4 CIL - Centre d-infection et d-immunité de Lille

Abstract : Ligands of pattern recognition receptors PRRs including Toll-like receptors TLRs stimulate innate and adaptive immune responses and are considered as potent adjuvants. Combinations of ligands might act in synergy to induce stronger and broader immune responses compared to stand-alone ligands. Alphaviruses stimulate endosomal TLRs 3, 7 and 8 as well as the cytoplasmic PRR MDA-5, resulting in induction of a strong type I interferon IFN response. Bacterial flagellin stimulates TLR5 and when delivered intracellularly the cytosolic PRR NLRC4, leading to secretion of proinflammatory cytokines. Both alphaviruses and flagellin have independently been shown to act as adjuvants for antigen-specific antibody responses. Here, we hypothesized that alphavirus and flagellin would act in synergy when combined. We therefore cloned the Salmonella Typhimurium flagellin FliC gene into an alphavirus replicon and assessed its adjuvant activity on the antibody response against co-administered antigen. In mice immunized with recombinant alphavirus, antibody responses were greatly enhanced compared to soluble FliC or control alphavirus. Both IgG1 and IgG2a-c responses were increased, indicating an enhancement of both Th1 and Th2 type responses. The adjuvant activity of FliC-expressing alphavirus was diminished but not abolished in the absence of TLR5 or type I IFN signaling, suggesting the contribution of several signaling pathways and some synergistic and redundant activity of its components. Thus, we have created a recombinant adjuvant that stimulates multiple signaling pathways of innate immunity resulting in a strong and broad antibody response.

Autor: Maria Knudsen - Daniel Johansson - Linda Kostic - Eva Nordström - Karin Tegerstedt - Anna Pasetto - Steven Applequist - Karl Lju



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