Contact Dependent Growth Inhibition in Burkholderia pseudomallei

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DESCRIPTION (provided by applicant): Burkholderia pseudomallei is a Gram-negative environmental saprotroph endemic to southeast Asia and northern Australia that causes melioidosis, a serious and often lethal human disease. Because it is far more prevalent than previously recognized and/or spreading beyond established boundaries, B. pseudomallei is a serious emerging global infectious disease problem. It is also a potential bioterrorism agent that has been classified as an NIAID Category B Priority Pathogen. The threat it presents is underscored by its extremely low infectious dose, its ability to initiate infection by an aerosol route, its intrinsic resistance to commonly used antibiotics, lack of a vaccine, lack of a rapid diagnostic test, and unfamiliarity of U.S. physicians with the disease. The development of point-of-care diagnostics, the identification of potential vaccine components, and the development of new therapeutics remain high priority goals. Contact Dependent Growth Inhibition (CDI) is a phenomenon discovered in a specific strain of Escherichia coli in which bacteria producing a large surface-localized protein called CdiA inhibit the growth of E. coli that do not produce CDI systems upon cell-cell contact. Our preliminary studies with B. pseudomallei revealed that CDI systems are widespread amongst Gram-negative bacteria and that they are polymorphic in the regions of the CdiA proteins that kill target cells and the immunity proteins that protect inhibitor cells. Variability is especially pronounced amongst B. pseudomallei strains. We propose to test the hypothesis that Burkholderia BtpAIB proteins function as allele-specific interbacterial CDI systems. We will determine if they function in an intra- and/or inter-species manner. We will also determine if the BtpAIB proteins contribute to B. pseudomallei and, if so, if CDI is required for that ability. Understanding how CDI systems function in B. pseudomallei will provide a deeper understanding of the molecular mechanisms underlying the pathogenic strategies used by these complicated pathogens and the information obtained may allow us to exploit CDI systems for the development of new approaches for treating melioidosis and eliminating B. pseudomallei from contaminated environments PUBLIC HEALTH RELEVANCE: Burkholderia pseudomallei, which causes the serious and often fatal disease melioidosis, is an emerging infectious disease pathogen and potential biowarfare agent for which we lack rapid diagnostics, effective therapeutics, and a vaccine. We will test the hypothesis that the B. pseudomallei btpAIB genes encode polymorphic interbacterial competition systems and that they play a role in virulence. Characterization of these systems may allow them to be developed as new types of anti-microbials for treating melioidosis and/or eliminating B. pseudomallei from contaminated environments.