Abstract
Persistent infections caused by pathogens such as hepatitis C virus are major human diseases with limited or suboptimal prophylactic and therapeutic options. Given the critical role of dendritic cell (DC) in inducing immune responses, DC vaccination is an attractive means to prevent and control the occurrence and persistence of the infections. However, DCs are built-in with inherent negative regulation mechanisms which attenuate their immune stimulatory activity and lead to their ineffectiveness in clinical application. In this study, we developed a super DC stimulant that consists of a modified, secretory Toll-like Receptor (TLR)-5 ligand and an inhibitor of the negative regulator, suppressor of cytokine sinaling-1 (SOCS1). We found that expressing the super stimulant in DCs is drastically more potent and persistent than using the commonly used DC stimuli to enhance the level and duration of inflammatory cytokine production by both murine and human DCs. Moreover, the DCs expressing the super stimulant are more potent to provoke both cellular and humoral immune responses against hepatitis C virus (HCV) antigen in vivo. Thus, the strategy capable of triggering and sustaining proinflammatory status of DCs may be used to boost efficiency of DC vaccine in preventing and combating the persistent infection of HCV or other chronic viruses.
Highlights
Intensive efforts have been devoted to develop Toll-like receptor (TLR) agonists to improve vaccine efficacy, since antigenpresenting cells (APCs), such as dendritic cells (DCs), use TLRs to sense conserved structural moieties of pathogens for the activation of proinflammatory signaling cascades, and innate/ adaptive immune responses [1,2,3]
Pathogens associated with chronic infections such as human immunodeficiency virus (HIV) and hepatitis C virus (HCV) are refractory to the immune responses that are induced either by vaccination or natural infection of pathogens that contain TLR ligands themselves
We found that all of the TLR ligands promoted the inflammatory status of Ad-shS1-transduced bone marrow-derived DCs (BMDCs) to different extents, and LPS-mediated cytokine production (TNF-a, IL-12p40, and IL-6) from Ad-shS1-transduced BMDCs nearly reached the same levels of the cytokines produced by Ad-shS1/FliC-transduced BMDCs (Fig. S6)
Summary
Intensive efforts have been devoted to develop Toll-like receptor (TLR) agonists to improve vaccine efficacy, since antigenpresenting cells (APCs), such as dendritic cells (DCs), use TLRs to sense conserved structural moieties of pathogens for the activation of proinflammatory signaling cascades, and innate/ adaptive immune responses [1,2,3]. TLR5 engagement by flagellin activates the MyD88-dependent signaling pathway, which leads to the activation of NF-kB and MAPKs, inducing the maturation of APCs and the secretion of proinflammatory cytokines and chemokines. In this study we designed and tested a super agonist of TLR, designated as super-TLR-agonist, consisting of FliC and a small inhibitory RNA of SOCS1, for triggering and sustaining TLR signaling and cytokine signaling cascades in DCs. The expression of the super-TLR-agonist in DCs is found more potent and persistent than using commercial TLR agonist as a maturation agent in stimulating the level and duration of inflammatory cytokine production by both murine and human DCs. the super-TLR-agonist-expressed DCs display a superior ability to activate HCV antigen-specific cellular and humoral immune responses
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