Francisella tularensis is a highly infectious Category A bacterial pathogen that causes tularemia, a potentially life-threatening disease in humans. Due to the ease of aerosol dissemination of this organism and the minimal inoculum (s10 bacteria) necessary to cause severe disease, F. tularensis has been weaponized for use in biowarfare. Critical to Francisella's pathogenesis are its ability to replicate within macrophages, the primary niche for replication in vivo, and to subvert the host immune response. Many genes contribute to the ability of bacterial pathogens to replicate within the host, but distinct immunomodulatory virulence factors, which are not required for replication, often play crucial roles in evading host immune responses. Unfortunately, relatively little is known about which genes F. tularensis uses to subvert host defenses and how these genes are regulated. We recently employed a powerful global in vivo negative selection screen in mice to identify genes required for the pathogenesis of Francisella. This approach resulted in the identification of 164 genes that are required for virulence, 44 of which appear to encode novel virulence factors. Among the genes encoding novel virulence factors were 2 that we showed are dispensable for bacterial replication within macrophages but play critical roles in suppressing the macrophage cell death response, an important host defense. We will1 screen mutants for each of the other 162 genes identified in our screen to identify those that are dispensable for bacterial replication in macrophages, but alter macrophage defense responses. We will determine how they contribute to the pathogenesis of virulent F. tularensis at the molecular level. Elucidation of the molecular mechanisms of action of critical F. tularensis virulence factors will significantly enhance our understanding of Francisella pathogenesis as well as common themes in host-pathogen interactions. This work will generate data that will lay the groundwork for the next generation of therapeutics and vaccines against potential biowarfare agents and emerging infections.

Public Health Relevance

We will determine ways in which pathogenic bacteria subvert the mammalian immune system in order to cause disease, focusing on Francisella, the bacterial causative agent of the disease tularemia and a biowarfare threat. This work will lead to the next generation of novel vaccines and therapeutics to treat nfections caused by biowarfare agents and new emerging infectious threats.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Specialized Center--Cooperative Agreements (U54)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of North Carolina Chapel Hill
Chapel Hill
United States
Zip Code
Smartt, Chelsea T; Shin, Dongyoung; Alto, Barry W (2017) Dengue serotype-specific immune response in Aedes aegypti and Aedes albopictus. Mem Inst Oswaldo Cruz 112:829-837
Purcell, Erin B; McKee, Robert W; Courson, David S et al. (2017) A Nutrient-Regulated Cyclic Diguanylate Phosphodiesterase Controls Clostridium difficile Biofilm and Toxin Production during Stationary Phase. Infect Immun 85:
Ponnuswamy, Padmapriya; Joffre, Jeremie; Herbin, Olivier et al. (2017) Angiotensin II synergizes with BAFF to promote atheroprotective regulatory B cells. Sci Rep 7:4111
Silva, Laurie A; Dermody, Terence S (2017) Chikungunya virus: epidemiology, replication, disease mechanisms, and prospective intervention strategies. J Clin Invest 127:737-749
Elong Ngono, Annie; Chen, Hui-Wen; Tang, William W et al. (2016) Protective Role of Cross-Reactive CD8 T Cells Against Dengue Virus Infection. EBioMedicine 13:284-293
Bowles, R D; Karikari, I O; VanDerwerken, D N et al. (2016) In vivo luminescent imaging of NF-?B activity and NF-?B-related serum cytokine levels predict pain sensitivities in a rodent model of peripheral neuropathy. Eur J Pain 20:365-76
Rowse, Michael; Qiu, Shihong; Tsao, Jun et al. (2016) Reduction of Influenza Virus Envelope's Fusogenicity by Viral Fusion Inhibitors. ACS Infect Dis 2:47-53
Ashbrook, Alison W; Lentscher, Anthony J; Zamora, Paula F et al. (2016) Antagonism of the Sodium-Potassium ATPase Impairs Chikungunya Virus Infection. MBio 7:
Bates, John T; Pickens, Jennifer A; Schuster, Jennifer E et al. (2016) Immunogenicity and efficacy of alphavirus-derived replicon vaccines for respiratory syncytial virus and human metapneumovirus in nonhuman primates. Vaccine 34:950-6
Alayli, Farah; Scholle, Frank (2016) Dengue virus NS1 enhances viral replication and pro-inflammatory cytokine production in human dendritic cells. Virology 496:227-236

Showing the most recent 10 out of 387 publications