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- W4313382685 abstract "Abstract Vaccines have enabled control of many deadly infectious diseases. However, efficacy in host protective immune responses vary greatly. Adjuvants targeting Toll like and cytosolic receptors can greatly enhance antigen-specific immunity. In this regard, pathogen-like micro-particles (PLP) co-loaded with TLR4 (MPLA) and/or TLR9 (CpG) ligands was used as a novel platform to deliver combinatorial adjuvants. We analyzed molecular signaling pathways activated in bone-marrow-derived dendritic cells (BMDCs) upon stimulation with PLPs, specifically leading to IFNb and IL-12p70 production. Stimulation of BMDCs with PLPs containing only MPLA or CpG resulted in low-level or no IFN-b and IL-12p70 release. However, stimulation of BMDCs with PLPs containing both MPLA and CpG triggered production of very high amounts of IFN-b and IL-12p70. Analysis of signaling pathways responsible for these results demonstrated IFN-b and IL12-p70 production in BMDCs harvested from WT, IRF3-KO, and IRF7-KO mice, but not from IRF5-KO animals. Exploration of IRF5 phosphorylation kinetics showed MPLA-loaded PLP transiently stimulated IRF5 (0.5 to 2 hours post stimulation) with dual adjuvant PLPs displaying a greatly prolonged p-IRF5, detectable even at 4 hours post stimulation. We are currently analyzing molecular regulators of p-IRF5 stability and kinetics of its translocation to the nucleus. Our study reveals an unexpected role for IRF5 in driving a highly potentiated production of immune-stimulatory cytokines from dendritic cells in response to dual MPLA and CpG adjuvants. These findings may help develop novel vaccines with improved efficacy when combined with PLPs loaded with MPLA and CpG adjuvants that activate IRF5-dependent cytokine production." @default.
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- W4313382685 date "2020-05-01" @default.
- W4313382685 modified "2023-10-16" @default.
- W4313382685 title "IRF5 Drives Potentiated IFN-beta and IL-12 production by dendritic cells in response to combinatorial CpG- and MPLA- delivery on microparticles" @default.
- W4313382685 doi "https://doi.org/10.4049/jimmunol.204.supp.166.6" @default.
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