Bacterial Lipopolysaccharide Structure

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Bacterial pathogens have evolved adaptive responses to the environmental changes encountered when they enter a host from an external reservoir. These responses include modifications of the bacterial cell envelope that enhance the ability to colonize, spread to different tissues, and avoid the hosts' normal defenses. The synthesis of accessory structures such as antiphagocytic capsules, adhesive fimbriae, and new integral membrane proteins are examples of host-associated surface modifications. Modifications to essential cell membrane components such as lipid A [the hydrophobic membrane anchor of lipopolysaccharide (LPS)], are important for pathogenesis. These and other virulence-related adaptations are often coordinately regulated via two-component signal sensing and transduction systems that respond to environmental changes (e.g., of temperature, osmotic pressure, pH, and concentrations of specific ions). In preliminary studies, we found that in response to a change of temperature during growth, from 21¿C to 37¿C, to mimic the bacterial "flea to mammal" (or external environment to mammal) life cycle, Yp synthesized unique lipid A structures. These environmentally-regulated lipid A structures conferred resistance to cationic antimicrobial peptides (CAP), and promote altered host inflammatory responses. Thus, temperature-dependent alteration of lipid A structure (to a less endotoxic form) upon entry into the mammalian host may represent a pathogenesis strategy common to the Yersiniae. This proposal contains experiments to define and to elucidate the mechanism of the synthesis of environmentally-regulated lipid A structures from Yersinia pestis, and to also define the lipid A structures of Francisella tularensis and Burkholderia pseudomallei, potential agents of bioterrorism. In addition, the role of these specific lipid A structures in affecting the innate immune system of the host will be determined. PERFORMANCE SITE(S) (organization, city, state) KEY PERSONNEL. See instructions. Use continuation pages as needed to provide the required information in the format shown below. Start with Principal Investigator. List all other key personnel in alphabetical order, last name first. Name Organization Role on Project Robert K. Ernst University of Washington, Seattle, WA PI Samuel I. Miller University of Washington, Seattle, WA Co-investigator Joseph Hinnebusch Rocky Mountain Laboratories, Hamilton, MT Collaborator Disclosure Permission Statement. Applicable to SBIR/STTR Only. See instructions. [] Yes [] No Pl-l.q _CI_ (I_,,_ N_ff1"l _nrm P_n_