Pseudomonas aeruginosa is an opportunistic bacterial pathogen that causes chronic lung infections associated with biofilm formation in the airways of cystic fibrosis (CF) and immune-compromised patients, including those with chronic wounds. Biofilms are structured communities of microbes encased within a matrix and exhibit resistance to antimicrobials and host defenses. It remains unclear how biofilm bacteria survive within the CF airways or the interplay of P. aeruginosa matrix materials with host immune cells. The focus of this application is on two critical components of the P. aeruginosa biofilm matrix biofilm matrix, an extracellular polysaccharide Psl and a protein adhesion CdrA. Our overall objective is to determine the roles of Psl and CdrA in biofilm structural integrity and tolerance o P. aeruginosa to antimicrobials and host defense.
Aim 1 will focus investigating structure- function relationships necessary for P. aeruginosa biofilm matrix integrity and define the roles of biofilm matrix components in modulating interactions of P. aeruginosa with human phagocytic cells. In the second aim we will define a novel signal transduction pathway responsible for a feed-forward mechanism of Psl-dependent signaling. There remain significant gaps in our understanding of how P. aeruginosa survive in the CF airway even in the presence of a robust immune response. Since the biofilm matrix provides a protective role, studies aimed at understanding the functions of matrix components will provide insights and therapeutic strategies aimed at early events of CF pathogenesis and other P. aeruginosa infections where biofilms are linked with human disease.

Public Health Relevance

Pseudomonas aeruginosa is a versatile opportunistic pathogen that can cause chronic pulmonary infection in cystic fibrosis (CF) patients and is also a key source of infection in immune-compromised patients. Within the CF airway, P. aeruginosa transforms into a resistant community called a biofilm. Inside the biofilm community, bacteria aggregate and cover themselves with a coating composed of sugar molecules (exopolysaccharides) and proteins. This application will define how these molecules provide structural integrity to the biofilm and how this relates to the recalcitrance of biofilm bacteria t host defenses. We will also define how one component of the biofilm matrix serves as a signaling molecule to communicate with other members of the biofilm community. The ultimate goal of the research is to enhance the interaction of host immune cells and biofilm forming P. aeruginosa so that biofilms can be eradicated from the CF lung as well as individuals with other P. aeruginosa infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI097511-02
Application #
8601164
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Taylor, Christopher E,
Project Start
2013-01-01
Project End
2017-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
2
Fiscal Year
2014
Total Cost
$346,552
Indirect Cost
$76,918
Name
Ohio State University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
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:
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:
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:
Chaney, Sarah B; Ganesh, Kasturi; Mathew-Steiner, Shomita et al. (2017) Histopathological comparisons of Staphylococcus aureus and Pseudomonas aeruginosa experimental infected porcine burn wounds. Wound Repair Regen 25:541-549
Jones, Christopher J; Wozniak, Daniel J (2017) Psl Produced by Mucoid Pseudomonas aeruginosa Contributes to the Establishment of Biofilms and Immune Evasion. MBio 8:
Hill, Preston J; Scordo, Julia M; Arcos, Jesús et al. (2017) Modifications of Pseudomonas aeruginosa cell envelope in the cystic fibrosis airway alters interactions with immune cells. Sci Rep 7:4761
Gunn, John S; Bakaletz, Lauren O; Wozniak, Daniel J (2016) What's on the Outside Matters: The Role of the Extracellular Polymeric Substance of Gram-negative Biofilms in Evading Host Immunity and as a Target for Therapeutic Intervention. J Biol Chem 291:12538-46
Armbruster, Catherine R; Wolter, Daniel J; Mishra, Meenu et al. (2016) Staphylococcus aureus Protein A Mediates Interspecies Interactions at the Cell Surface of Pseudomonas aeruginosa. MBio 7:

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