Francisella tularensis subspecies tularensis, also known as type A Francisella, is a category A priority pathogen for Biodefense Research. It causes a potentially life-threatening disease called tularemia. F. tularensis is a low dose pathogen; infection with less than 10 organisms can cause a lethal infection. A novel F. tularensis lipoprotein, designated Francisella infectivity potentiator B (FipB) in the type A Schu S4 strain has been shown to be essential for virulence. The goal of this proposal is to characterize the role of FipB in virulence and identify critical aspects of F. tularensis pathogenicity. Because FipB is essential for virulence in a type A strain, the experiments described in this proposal will have a significant impact on our understanding of the processes and pathways of F. tularensis that are essential for virulence. FipB has several features that can be used to investigate its function in virulence. As a lipoprotein, it has been shown to stimulate the innate receptor TLR2. Bioinformatic analyses indicate that FipB two conserved domains. One domain shares sequence and structural similarity with a class of virulence proteins called Mips (macrophage infectivity potentiator). The other domain is the conserved enzymatic active site of the DsbA class of oxidoreductases, that have been shown to be required for the formation of virulence factors in other Gram-negative bacteria. Specific deletions and site-specific mutations of fipB will be created in order to define the regions and features of FipB that are required for internalization and intracellular survival. Identifying the critical functional domains of FipB will aid in development drugs that target the critical regions of this novel protein; characterizing the virulence pathway may also identify additional targets for new therapies.

Public Health Relevance

Understanding the roles of Francisella tularensis virulence factors in the ability to cause disease will have practical applications for the development of attenuated vaccines, and in the identification of new targets for antibiotics.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
High Priority, Short Term Project Award (R56)
Project #
1R56AI091746-01
Application #
8321699
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Mukhopadhyay, Suman
Project Start
2011-09-01
Project End
2013-08-31
Budget Start
2011-09-01
Budget End
2013-08-31
Support Year
1
Fiscal Year
2011
Total Cost
$382,641
Indirect Cost
Name
University of Virginia
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904