The virulence of a bacterium is closely linked to its ability to release secreted factors. It follows that many evolutionarily distinct pathways exist for the translocation of proteins in pathogenic Gram-negative bacteria (types I-VI). Type VI secretion (T6S), the most recently described of these pathways, is an important contributor to the virulence of many pathogenic bacteria. The PI of this proposal, Dr. Joseph Mougous, first characterized this secretion system in Pseudomonas aeruginosa. This work produced fundamental biochemical and structural insights into the secretion system;furthermore, it provided evidence that the T6S system (T6SS) of P. aeruginosa is important for the devastating chronic infections this organism causes in cystic fibrosis patients. The focus of this proposal, and the major research emphasis of Dr. Mougous' laboratory, is to understand the regulatory pathway that tightly modulates the activity of the P. aeruginosa T6SS. This pathway, which is reminiscent of eukaryotic signaling, is initiated by dimerization of a transmembrane serine-threonine kinase. This provokes a series of events that "triggers" the secretion system, leading to substrate translocation. Although prior work by Dr. Mougous has revealed some of the mechanistic details of this pathway, many key questions remain unanswered. The proposed experiments seek to answer these mechanistic questions, and also to utilize this novel mode of regulation for the purpose of identifying substrates of the secretion system - a current impediment to the field. Many pathogens of significance to human health and biodefense require T6S for virulence and use this pathway to regulate its activity;therefore, findings generated by the proposed research will have broad implications and could lead to the development of new therapeutic strategies.

Public Health Relevance

Pathogenic bacteria utilize protein secretion to cause disease. The aims of this proposal investigate how one type of protein secretion, type VI secretion (T6S), is regulated in the opportunistic human pathogen Pseudomonas aeruginosa. The proposed research also seeks to understand what factors released by T6S contribute to its role in chronic P. aeruginosa infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI080609-05
Application #
8467667
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Taylor, Christopher E,
Project Start
2009-06-17
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2013
Total Cost
$339,615
Indirect Cost
$109,291
Name
University of Washington
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Whitney, John C; Beck, Christina M; Goo, Young Ah et al. (2014) Genetically distinct pathways guide effector export through the type VI secretion system. Mol Microbiol 92:529-42
Russell, Alistair B; Wexler, Aaron G; Harding, Brittany N et al. (2014) A type VI secretion-related pathway in Bacteroidetes mediates interbacterial antagonism. Cell Host Microbe 16:227-36
Russell, Alistair B; Peterson, S Brook; Mougous, Joseph D (2014) Type VI secretion system effectors: poisons with a purpose. Nat Rev Microbiol 12:137-48
Casabona, Maria G; Silverman, Julie M; Sall, Khady M et al. (2013) An ABC transporter and an outer membrane lipoprotein participate in posttranslational activation of type VI secretion in Pseudomonas aeruginosa. Environ Microbiol 15:471-86
Whitney, John C; Chou, Seemay; Russell, Alistair B et al. (2013) Identification, structure, and function of a novel type VI secretion peptidoglycan glycoside hydrolase effector-immunity pair. J Biol Chem 288:26616-24
Silverman, Julie M; Agnello, Danielle M; Zheng, Hongjin et al. (2013) Haemolysin coregulated protein is an exported receptor and chaperone of type VI secretion substrates. Mol Cell 51:584-93
Russell, Alistair B; LeRoux, Michele; Hathazi, Krisztina et al. (2013) Diverse type VI secretion phospholipases are functionally plastic antibacterial effectors. Nature 496:508-12
Li, Mo; Le Trong, Isolde; Carl, Mike A et al. (2012) Structural basis for type VI secretion effector recognition by a cognate immunity protein. PLoS Pathog 8:e1002613
Russell, Alistair B; Hood, Rachel D; Bui, Nhat Khai et al. (2011) Type VI secretion delivers bacteriolytic effectors to target cells. Nature 475:343-7
Silverman, Julie M; Austin, Laura S; Hsu, FoSheng et al. (2011) Separate inputs modulate phosphorylation-dependent and -independent type VI secretion activation. Mol Microbiol 82:1277-90

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