Bacterial populations have the ability to generate persister cells that can tolerate exposure to lethal doses of antibiotics and persistence may be responsible for relapses seen after standard antibiotic treatments of bacterial infections. Francisella tularensis is a Gram-negative bacterium that causes the deadly disease of tularemia and is commonly spread by ticks in the US. It is highly infectious and is classified as a Tier1 Select agent by the DHHS and the CDC. F. tularensis enters and replicates in the cytoplasm of different host cells including macrophages, overcoming nutritional and other stresses in this environment. Tularemia treatment with standard antibiotic therapy may result in relapse and there is a great need for development of adjunct therapy to combat infection with this pathogen. Understanding the mechanisms that govern persister formation is therefore critical. In the well-studied model organism Escherichia coli, development of persister cells is regulated by the hipBA locus in conjunction with ten other toxin-antitoxin (TA) loci. This proposal has three aims that will test if F. tularensis forms persisters in response to signals received by hipBA in the mammalian intracellular environment.
Aim 1 will examine whether the intracellular environment influences persistence.
Aim 2 of this proposal will explore the role of the hipBA genes in persistence of F. tularensis.
Aim 3 will seek to identify signals and pathways that regulate persister cell formation. Understanding the mechanisms of hipBA- mediated persistence in this organism may lead to identification of targets for development of new adjunct therapies directed at persisters.

Public Health Relevance

Bacterial infections are typically treated with antibiotics, but even with the recommended treatment regimens, relapses of infection do occur due to the ability of some of the bacteria to persist and reestablish infection. This proposal will use the bacterium Francisella tularensis as a model organism to understand the signals and pathways that direct bacteria to develop into persister cells that can tolerate antibiotic treatment. Understanding these processes can lead to development of new therapies aimed at preventing relapses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI119471-01A1
Application #
9110644
Study Section
Special Emphasis Panel (ZRG1-IDM-B (80)S)
Program Officer
Mukhopadhyay, Suman
Project Start
2016-07-14
Project End
2018-06-30
Budget Start
2016-07-14
Budget End
2017-06-30
Support Year
1
Fiscal Year
2016
Total Cost
$237,000
Indirect Cost
$87,000
Name
University of Virginia
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904