Burkholderia pseudomallei, the causative agent of melioidosis, is an NIAID Category B priority pathogen. It causes serious and often lethal human disease and represents both a worldwide emerging infectious disease problem and a bioterrorism threat due to its extremely low infectious dose, the ability to initiate infection by an aerosol route, an intrinsic resistance to commonly used antibiotics and the lack of a currently available vaccine. Little is known about the molecular bases of B. pseudomallei pathogenesis. The overall goals of this project are to determine the roles and regulation of adhesins and type III secretion in the establishment of infection and induction of innate and adaptive immune responses by B. pseudomallei. Project 1 will use targeted and random mutagenesis approaches to identify and characterize B. pseudomallei adhesins, including fimbrial homologues identified in the genome. Regulatory loci will be identified, characterized and used to identify additional virulence genes. In Project 2 animal models to investigate infection and immunity will be developed. These models will be used by all projects and therefore represent an essential core resource for the entire program project. A second goal of Project 2 is to determine the contribution to pathogenesis of the filamentous hemagglutinin (FHA) hornolog present in B. pseudomallei. The goals of Project 3 are to conduct a comprehensive assessment of the role in pathogenesis of B. pseudomallei type III secretion systems and to use an understanding of their regulation to identify additional unlinked virulence factors. Project 4 is aimed at understanding the role of the interferon system in the host response to B. pseudomallei infection. The roles of specific adhesins and type III secretion in the interferon response will be determined. These projects represent a cohesive effort to understand the molecular mechanisms involved in the establishment of infection and immunity by B. pseudomallei which will lead the way for the development of new vaccines and therapeutics for the prevention and treatment of disease.
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