Bacterial quorum sensing involves small molecule cell-cell siganling that allows coordination of behavior among individual cells in a population. Quorum sensing in the NIAID Category B Priority Pathogen Burkholderia mallei holds a particular interest. First, like for certain other pathogens such as Pseudomonas aeruginosa quorum sensing is involved in virulence of B. mallei. Efforts to develop anti-Pseudomonas quorum sensing inhibitors have been hindered by the lack of adequate animal models for Pseud0monas infections. The availability of such models for B. mallei affords us the ability to put a program in motion that will eventually lead to tests of efficacy for small molecule inhibitors in animal models. Second, a common belief among scientists working on quorum sensing is that it allows a pathogen (or at least a symbiont) to discriminate between a host and a free-living state, Burkholderia mallei is an obligate animal pathogen with no known environmental reservoir. Quorum sensing must be involved in discrimination of different stages or types of infections by this pathogen. Finally, a most obviously, quorum sensing in B. Mallei is a target for anti-S. mallei therapeutic development. Dr. Greenberg proposes to adapt his recently developed quorum sensing reporter system for use in a high-throughput screen for inhibitors. Further experiments will be aimed at identification of quorum-controlled fi. mallei genes. These experiments will involve promoter-trap technology and require the construction of a quorum-sensing regular """"""""gutted strain of B. mallei and or the closely related fi. thailandensis. A new counter-selection method for insertional gene inactiviation in B. thailandensis will be described, as will plans to extend the procedure to B. meillei. This method for generating mutations in members of the B. mallei group represents a major advance that will overcome a current obstacle faced by fi. mallei biologists.
The project will enhance our understanding of virulence in the NIAID Category B Priority Pathogen Burkholderia mallei. The research will shed light on the genetic regulation of virulence factors. Moreover, the research will move towards development of inhibitors of fi. mallei virulence. Obviously, such inhibitors may prove useful as therapeutic agents. The investigations may lead to similar agents for other pathogens.
|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:|
|Miller, Samuel I; Chaudhary, Anu (2016) A Cellular GWAS Approach to Define Human Variation in Cellular Pathways Important to Inflammation. Pathogens 5:|
|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|
|Jorgensen, Ine; Lopez, Joseph P; Laufer, Stefan A et al. (2016) IL-1Î², IL-18, and eicosanoids promote neutrophil recruitment to pore-induced intracellular traps following pyroptosis. Eur J Immunol 46:2761-2766|
|Chapman, John D; Edgar, J Scott; Goodlett, David R et al. (2016) Use of captive spray ionization to increase throughput of the data-independent acquisition technique PAcIFIC. Rapid Commun Mass Spectrom 30:1101-7|
|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|
|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|
|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|
|Salipante, Stephen J; Roach, David J; Kitzman, Jacob O et al. (2015) Large-scale genomic sequencing of extraintestinal pathogenic Escherichia coli strains. Genome Res 25:119-28|
|Maltez, Vivien I; Tubbs, Alan L; Cook, Kevin D et al. (2015) Inflammasomes Coordinate Pyroptosis and Natural Killer Cell Cytotoxicity to Clear Infection by a Ubiquitous Environmental Bacterium. Immunity 43:987-97|
Showing the most recent 10 out of 240 publications