Bacterial pathogens have evolved adaptive responses to the environmental changes encountered when theyenter a host from an external reservoir. These responses include modifications of the bacterial cell envelopethat enhance the ability to colonize, spread to different tissues, and avoid the hosts' normal defenses. Thesynthesis of accessory structures such as antiphagocytic capsules, adhesive fimbriae, and new integralmembrane proteins are examples of host-associated surface modifications. Modifications to essential cellmembrane components such as lipid A [the hydrophobic membrane anchor of lipopolysaccharide (LPS)], areimportant for pathogenesis. These and other virulence-related adaptations are often coordinately regulatedvia two-component signal sensing and transduction systems that respond to environmental changes (e.g., oftemperature, osmotic pressure, pH, and concentrations of specific ions). In preliminary studies, we foundthat in response to a change of temperature during growth, from 21 C to 37 C, to mimic the bacterial 'flea tomammal' (or external environment to mammal) life cycle, Yp synthesized unique lipid A structures. Theseenvironmentally-regulated lipid A structures conferred resistance to cationic antimicrobial peptides (CAP),and promote altered host inflammatory responses. Thus, temperature-dependent alteration of lipid Astructure (to a less endotoxic form) upon entry into the mammalian host may represent a pathogenesisstrategy common to the Yersiniae.This proposal contains experiments to define and to elucidate the mechanism of the synthesis ofenvironmentally-regulated lipid A structures from Yersinia pestis, and to also define the lipid A structures ofFrancisella tularensis and Burkholderia pseudomallei, potential agents of bioterrorism. In addition, the roleof 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 ProjectRobert K. Ernst University of Washington, Seattle, WA PISamuel I. Miller University of Washington, Seattle, WA Co-investigatorJoseph Hinnebusch Rocky Mountain Laboratories, Hamilton, MT CollaboratorDisclosure Permission Statement. Applicable to SBIR/STTR Only. See instructions. [] Yes [] NoPl-l.q _CI_ (I_,,_ N_ff1'l _nrm P_n_
Showing the most recent 10 out of 247 publications
