An important feature of Pseudomonas aeruginosa pathogenesis is the ability to form surface- associated communities called biofilms. Several types of P. aeruginosa infections are characterized by biofilm formation, including the colonization of indwelling medical devices and the chronic infections present in the airways of people suffering from cystic fibrosis (CF). Biofilm bacteria produce one or more extracellular polymeric substances (EPS) that act as a scaffold, holding biofilm cells together and to a surface. For some time, alginate has been considered the major polysaccharide of the P. aeruginosa EPS biofilm matrix. Recently, our studies indicate that alginate is not a significant component of the EPS matrix of nonmucoid strains, which are responsible for most opportunistic biofilm infections and are also the first to colonize CF patients. Instead, there appear to be other EPS components that mediate biofilm formation. Our lab and others discovered that P. aeruginosa has the capacity to encode two alternative polysaccharides, designated Psl and Pel, which play critical roles in cell surface interactions and biofilm formation. The focus of this proposal is the Pel gene cluster. Our overall objective is to determine the role of Pel in biofilm development, structure, resistance to antimicrobial agents, and pathogenesis. A further understanding of this critical biofilm component will lead to strategies aimed at inhibiting biofilm formation, a key aspect of P. aeruginosa pathogenesis. Despite significant advancements in our knowledge of P. aeruginosa biofilm development, there remain gaps in our understanding of the biofilm matrix composition, as well as the genes responsible for producing this matrix. We have discovered a novel EPS locus that is essential for formation of P. aeruginosa biofilms. Since the matrix provides a critical protective role as well as a scaffold for the developing biofilm, agents aimed at disrupting the matrix would have therapeutic value. A thorough analysis of Pel may lead to the development of such agents and improve the quality of life for C patients as well as individuals with other P. aeruginosa infections that involve biofilms.

Public Health Relevance

is proposal is focused on examining the role of the important biofilm exopolysaccharide Pel in Pseudomonas aeruginosa biofilm formation and pathogenesis. The role of Pel in polysaccharide production, biofilm formation and pathogenesis will be explored.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI077628-02
Application #
7893711
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Taylor, Christopher E,
Project Start
2009-07-17
Project End
2013-06-30
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
2
Fiscal Year
2010
Total Cost
$502,350
Indirect Cost
Name
University of Washington
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Pestrak, Matthew J; Chaney, Sarah B; Eggleston, Heather C et al. (2018) Pseudomonas aeruginosa rugose small-colony variants evade host clearance, are hyper-inflammatory, and persist in multiple host environments. PLoS Pathog 14:e1006842
Tseng, Boo Shan; Reichhardt, Courtney; Merrihew, Gennifer E et al. (2018) A Biofilm Matrix-Associated Protease Inhibitor Protects Pseudomonas aeruginosa from Proteolytic Attack. MBio 9:
Reichhardt, Courtney; Wong, Cynthis; Passos da Silva, Daniel et al. (2018) CdrA Interactions within the Pseudomonas aeruginosa Biofilm Matrix Safeguard It from Proteolysis and Promote Cellular Packing. MBio 9:
Armbruster, Catherine R; Parsek, Matthew R (2018) New insight into the early stages of biofilm formation. Proc Natl Acad Sci U S A 115:4317-4319
Malhotra, Sankalp; Limoli, Dominique H; English, Anthony E et al. (2018) Mixed Communities of Mucoid and Nonmucoid Pseudomonas aeruginosa Exhibit Enhanced Resistance to Host Antimicrobials. MBio 9:
Marmont, Lindsey S; Rich, Jacquelyn D; Whitney, John C et al. (2017) Oligomeric lipoprotein PelC guides Pel polysaccharide export across the outer membrane of Pseudomonas aeruginosa. Proc Natl Acad Sci U S A 114:2892-2897
Amoh, Takashi; Murakami, Keiji; Kariyama, Reiko et al. (2017) Effects of an autoinducer analogue on antibiotic tolerance in Pseudomonas aeruginosa. J Antimicrob Chemother 72:2230-2240
Passos da Silva, Daniel; Schofield, Melissa C; Parsek, Matthew R et al. (2017) An Update on the Sociomicrobiology of Quorum Sensing in Gram-Negative Biofilm Development. Pathogens 6:
Snarr, Brendan D; Baker, Perrin; Bamford, Natalie C et al. (2017) Microbial glycoside hydrolases as antibiofilm agents with cross-kingdom activity. Proc Natl Acad Sci U S A 114:7124-7129
Marmont, Lindsey S; Whitfield, Gregory B; Rich, Jacquelyn D et al. (2017) PelA and PelB proteins form a modification and secretion complex essential for Pel polysaccharide-dependent biofilm formation in Pseudomonas aeruginosa. J Biol Chem 292:19411-19422

Showing the most recent 10 out of 33 publications