This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The initial intent of this study was to identify if innate immune agonists under study in our laboratory could affect the outcome of dengue virus infection. Oligomeric procyanidins (OPCs) found in the dietary supplement Applepoly quickly emerged as the most effective antiviral agent. Similar to published accounts, OPCs exhibited direct antiviral activity. The possibility of enhanced innate immune protection was also tested by measuring and characterizing gene and protein expression induced by OPCs during Dengue virus infection. Treatment of Dengue virus-infected human peripheral blood mononuclear cells (PBMC) with OPCs decreased viral titers and affected the expression of critical innate antiviral immune products. OPCs enhanced expression of MXI and interferon ? (IFN-?) transcripts in high multiplicity of infection (MOI) Dengue virus infected PBMC cultures, and phosphorylation of STAT2 in response to recombinant type I IFN (i.e., IFN-?). During low MOI infection, addition of OPCs increased expression of STAT1 transcripts, MHC I and tumor necrosis factor ? (TNF-?) protein production. Thus, OPCs exhibited innate immune stimulation of cells in Dengue virus-infected cultures and uninfected cells treated with type I IFN. While OPCs from a number of sources are known to exhibit antiviral effects, their mechanisms are not precisely defined. The capacity of OPCs to increase sensitivity to type I IFN could be broadly applicable to many viral infections and two separate antiviral mechanisms suggest that OPCs may represent a novel, robust antiviral therapy. Based on these data, we have begun to test the effects of OPCs in vivo in mice and human subjects.
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