P. aeruginosa is a common cause of hospital-acquired infections. It uses a type III secretion system to directly inject effector proteins into targeted host cells, in particular neutrophils, thereby preventing clearance by the host immune system. Injection of effector proteins involves a specialized structure called the translocon, which consists of a pore in the host cell membrane that interacts with the tip of the type III secretion needle. While the translocon is critical for type III secretion function, it has been difficult to study biochemically. Here we propose to use a genetic technique to identify critical translocator interactions and categorize them according to their function in the translocation process (translocator insertion, pore formation, docking of the tip to the pore and triggering of effector secretion). Identifying translocator contacts that are critical for function not only increases our understanding of the translocon, it also identifies potential targets for therapeutic intervention that lie outside of the bacterial cell and are therefore not shielded by conventional antibiotic resistance mechanisms, such as the outer membrane or efflux pumps.

Public Health Relevance

P. aeruginosa is a common cause of hospital-acquired disease with a high rate of mortality. It uses a molecular syringe to inactivate the patient's immune system. We are proposing to study the function of a critical component of this syringe, which lies on the outside of the bacterial cell and therefore represents an attractive target for drug development.

Agency
National Institute of Health (NIH)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI107131-01A1
Application #
8701601
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Taylor, Christopher E,
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
City
Cleveland
State
OH
Country
United States
Zip Code
44106