The most worrisome infectious agents of bioterrorism are those that would be artificially disseminated as aerosols to the lungs where the immune responses are unique, primarily driven by an immunoregulatory program. Critical mediators of the immune response in this environment are alveolar macrophages (AM) and epithelial cells. Francisella tularensis (Ft), a targeted infectious agent of bioterrorism, is an intracellular pathogen which causes acute life-threatening disease, particularly when transmitted via aerosols. The eukaryotic and microbial factors mediating host cell recognition and response for Ft remain poorly defined and their definition will be required for the rational development of new therapies and vaccines. This competitive renewal of RP9 unites an established group of collaborative scientists from the Ohio State University, Medical College of Wisconsin and University of Cincinnati to focus on the molecular pathogenesis of pneumonic tularemia. Based on recently published work and preliminary data, our central hypothesis is that Ft's success as a human pathogen is linked to its ability to suppress and/or subvert important elements of the protective innate immune response during the early phase of infection. To test this hypothesis we will 1) further define the molecular mechanisms that mediate Ft entry, intracellular trafficking, antimicrobial responses and initiation of the inflammatory program both in vitro and in vivo;2) construct, validate, and probe global microbial and host genetic screening platforms to identify key determinants mediating Ftinduced immune suppression and/or subversion;and 3) use targeted genetic approaches to identify novel Ft virulence determinants focusing on bacterial transcriptional regulators and Ft and host factors involved in Fe metabolism, including those of the bacterial oxidative stress response. Collectively, these studies will provide important new insights into host-pathogen interactions by the most virulent Ft subspecies, and will use novel mutant derivatives and relevant model systems of infection. This RP will synergize the talents of its investigators to place itself in the most competitive position to make fundamental discoveries related to pathogenic mechanisms for Ft, and begin to translate these discoveries into product development.

Public Health Relevance

Francisella tularensis (Ft) can cause an acute life-threatening pneumonia. The factors mediating infection remain poorly defined. This program will synergize the talents of investigators from the Ohio State University, Medical College of Wisconsin and University of Cincinnati to make fundamental discoveries related to how Ft is able to be a successful pathogen, and begin to translate these discoveries into product development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54AI057153-09
Application #
8376944
Study Section
Special Emphasis Panel (ZAI1-DDS-M)
Project Start
Project End
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
9
Fiscal Year
2012
Total Cost
$600,008
Indirect Cost
$113,853
Name
University of Chicago
Department
Type
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Sloup, Rudolph E; Konal, Ashley E; Severin, Geoffrey B et al. (2017) Cyclic Di-GMP and VpsR Induce the Expression of Type II Secretion in Vibrio cholerae. J Bacteriol 199:
Chen, Grischa Y; McDougal, Courtney E; D'Antonio, Marc A et al. (2017) A Genetic Screen Reveals that Synthesis of 1,4-Dihydroxy-2-Naphthoate (DHNA), but Not Full-Length Menaquinone, Is Required for Listeria monocytogenes Cytosolic Survival. MBio 8:
Coulson, Garry B; Johnson, Benjamin K; Zheng, Huiqing et al. (2017) Targeting Mycobacterium tuberculosis Sensitivity to Thiol Stress at Acidic pH Kills the Bacterium and Potentiates Antibiotics. Cell Chem Biol 24:993-1004.e4
Hollands, Andrew; Corriden, Ross; Gysler, Gabriela et al. (2016) Natural Product Anacardic Acid from Cashew Nut Shells Stimulates Neutrophil Extracellular Trap Production and Bactericidal Activity. J Biol Chem 291:13964-73
Kuhn, Misty L; Alexander, Evan; Minasov, George et al. (2016) Structure of the Essential Mtb FadD32 Enzyme: A Promising Drug Target for Treating Tuberculosis. ACS Infect Dis 2:579-591
Duckworth, Benjamin P; Wilson, Daniel J; Aldrich, Courtney C (2016) Measurement of Nonribosomal Peptide Synthetase Adenylation Domain Activity Using a Continuous Hydroxylamine Release Assay. Methods Mol Biol 1401:53-61
Park, Sung Ryeol; Tripathi, Ashootosh; Wu, Jianfeng et al. (2016) Discovery of cahuitamycins as biofilm inhibitors derived from a convergent biosynthetic pathway. Nat Commun 7:10710
Agostoni, Marco; Waters, Christopher M; Montgomery, Beronda L (2016) Regulation of biofilm formation and cellular buoyancy through modulating intracellular cyclic di-GMP levels in engineered cyanobacteria. Biotechnol Bioeng 113:311-9
Völlger, Lena; Akong-Moore, Kathryn; Cox, Linda et al. (2016) Iron-chelating agent desferrioxamine stimulates formation of neutrophil extracellular traps (NETs) in human blood-derived neutrophils. Biosci Rep 36:
Le, J; Dam, Q; Schweizer, M et al. (2016) Effects of vancomycin versus nafcillin in enhancing killing of methicillin-susceptible Staphylococcus aureus causing bacteremia by human cathelicidin LL-37. Eur J Clin Microbiol Infect Dis 35:1441-7

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