Pathogenic bacteria make extensive use of secreted proteins in order to colonize and persist in their hosts. Recently, a type VI protein secretion system (T6SS) of Burkholderia pseudomallei, the causative agent of melioidosis, was shown to be a major virulence determinant of the organism. The mechanistic basis for the role of T6S in B. pseudomallei whence is not known. Interestingly, the genome of this organism encodes five additional T6SSs that have not been investigated;accounting for greater than 2% of its genomic coding capacity. Given the widespread relevance of this protein translocation system in bacteria-host interactions, it is likely that these additional T6SSs also play critical roles for this organism. Having discovered T6S in the closely related organism Pseudomonas aeruginosa, the project leader of this proposal, Dr. Joseph Mougous, has demonstrated expertise in this field of research. The focus of this proposal is to characterize several aspects of the T6SSs of B. pseudomallei.
In Aim 1, the involvement of each system in virulence and host interactions will be measured.
Aim 2 will identify regulatory pathways of the systems, and investigate the role of a predicted post-translational control mechanism. In the final aim, novel T6S substrates will be identified by a quantitative mass spectrometric approach. The phenotypic profile of each secretion system, the identification of regulators, and the identities of T6S substrates, will provide a solid foundation for future investigation of T6S in this organism.

Public Health Relevance

Burkholderia pseudomallei is classified as a category B select agent by the CDC. The studies outlined in this proposal seek to understand how type VI protein secretion, an essential virulence determinant of B. pseudomallei, is utilized to promote disease. These studies will lead to the identification of pathways that could be targeted for therapeutic intervention.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Specialized Center--Cooperative Agreements (U54)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Washington
United States
Zip Code
Hagar, Jon A; Edin, Matthew L; Lih, Fred B et al. (2017) Lipopolysaccharide Potentiates Insulin-Driven Hypoglycemic Shock. J Immunol 199:3634-3643
Hajjar, Adeline M; Ernst, Robert K; Yi, Jaehun et al. (2017) Expression level of human TLR4 rather than sequence is the key determinant of LPS responsiveness. PLoS One 12:e0186308
Jorgensen, Ine; Lopez, Joseph P; Laufer, Stefan A et al. (2016) IL-1?, IL-18, and eicosanoids promote neutrophil recruitment to pore-induced intracellular traps following pyroptosis. Eur J Immunol 46:2761-2766
Miller, Samuel I; Chaudhary, Anu (2016) A Cellular GWAS Approach to Define Human Variation in Cellular Pathways Important to Inflammation. Pathogens 5:
Fan, Vincent S; Gharib, Sina A; Martin, Thomas R et al. (2016) COPD disease severity and innate immune response to pathogen-associated molecular patterns. Int J Chron Obstruct Pulmon Dis 11:467-77
Jorgensen, Ine; Zhang, Yue; Krantz, Bryan A et al. (2016) Pyroptosis triggers pore-induced intracellular traps (PITs) that capture bacteria and lead to their clearance by efferocytosis. J Exp Med 213:2113-28
Hayden, Hillary S; Matamouros, Susana; Hager, Kyle R et al. (2016) Genomic Analysis of Salmonella enterica Serovar Typhimurium Characterizes Strain Diversity for Recent U.S. Salmonellosis Cases and Identifies Mutations Linked to Loss of Fitness under Nitrosative and Oxidative Stress. MBio 7:e00154
Chaudhary, Anu; Leite, Mara; Kulasekara, Bridget R et al. (2016) Human Diversity in a Cell Surface Receptor that Inhibits Autophagy. Curr Biol 26:1791-801
Majerczyk, Charlotte; Schneider, Emily; Greenberg, E Peter (2016) Quorum sensing control of Type VI secretion factors restricts the proliferation of quorum-sensing mutants. Elife 5:
Yen, Gloria S; Edgar, J Scott; Yoon, Sung Hwan et al. (2016) Polydimethylsiloxane microchannel coupled to surface acoustic wave nebulization mass spectrometry. Rapid Commun Mass Spectrom 30:1096-100

Showing the most recent 10 out of 247 publications