Antioxidant Botanicals and Antimicrobial Defense

The primary aim ofthis project is to conduct pre-clinical screening of selected antioxidant botanicals for their potential to modulate in vivo anti-microbial and anti-viral activity. Crude extracts as well as putative bioactive components of each botanical will be tested both in vivo and in vitro.<P> Two murine bacterial infection models (i.e., co//-mediated sepsis and systemic listeriosis) and a novel murine HIV model will be used. Clinically relevant outcomes, such as fever, food intake, lethargy, and bacterial/viral clearance will be monitored along with a common set of inflammation/infection biomarkers (e.g., TNF-a, IL-ip, IL-6, MCP-1, IL-12, IL-10).<P> The working hypothesis is that botanicals with potent antioxidant activity will affect the redox status of host phagocytes such that inflammatory, anti-bacterial and anti-viral responses will be altered. As a consequence of this altered cellular redox the host will experience discernable benefits (e.g., lower fever, enhanced pathogen clearance, reduced systemic inflammation). <P> Exciting and novel preliminary findings show that Sutheriandia and elderberry extracts affect bacterial clearance and survival in the coli sepsis model. A murine macrophage cell line, RAW 264.7 cells, will be used to profile alterations in cellular events of importance to the inflammatory, anti-bacterial, and anti-viral pathways in response to the botanical compounds including: NADPH oxidase (NOX) and inducible nitric oxide synthase (INOS) activity, NF-KB activation and Nri'2-Keapl signaling. <P> Additionally, mice with a conditional deletion of Keapl in cells from the myeloid lineage (i.e., phagocytes) will be used to evaluate the interaction between Nrf2-dependent gene expression and antioxidant botanicals in shaping host response to infection. Mice with a myeloid-specific deletion of Keapl should have greatly enhanced Nri'2 signaling in phagocytes such that redox status within these innate immune cells is altered resulting in diminished inflammation. These unique mice will be used to explore interactions between Nrf2 signaling in phagocytes and effects of various botanicals on the innate immune system and the host response to infection.