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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54AI057157-11
Application #
8437247
Study Section
Special Emphasis Panel (ZAI1-DDS-M)
Project Start
Project End
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
11
Fiscal Year
2013
Total Cost
$426,466
Indirect Cost
$69,353
Name
University of North Carolina Chapel Hill
Department
Type
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Ashbrook, Alison W; Lentscher, Anthony J; Zamora, Paula F et al. (2016) Antagonism of the Sodium-Potassium ATPase Impairs Chikungunya Virus Infection. MBio 7:
Bowles, R D; Karikari, I O; VanDerwerken, D N et al. (2016) In vivo luminescent imaging of NF-κB activity and NF-κB-related serum cytokine levels predict pain sensitivities in a rodent model of peripheral neuropathy. Eur J Pain 20:365-76
Alayli, Farah; Scholle, Frank (2016) Dengue virus NS1 enhances viral replication and pro-inflammatory cytokine production in human dendritic cells. Virology 496:227-36
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
Fibriansah, Guntur; Tan, Joanne L; Smith, Scott A et al. (2015) A highly potent human antibody neutralizes dengue virus serotype 3 by binding across three surface proteins. Nat Commun 6:6341
de St Maurice, Annabelle; Grijalva, Carlos G; Fonnesbeck, Christopher et al. (2015) Racial and Regional Differences in Rates of Invasive Pneumococcal Disease. Pediatrics 136:e1186-94
Roberts, Lydia M; Ledvina, Hannah E; Tuladhar, Shraddha et al. (2015) Depletion of alveolar macrophages in CD11c diphtheria toxin receptor mice produces an inflammatory response. Immun Inflamm Dis 3:71-81
Smith, Scott A; Silva, Laurie A; Fox, Julie M et al. (2015) Isolation and Characterization of Broad and Ultrapotent Human Monoclonal Antibodies with Therapeutic Activity against Chikungunya Virus. Cell Host Microbe 18:86-95
Pulendran, Bali (2015) The varieties of immunological experience: of pathogens, stress, and dendritic cells. Annu Rev Immunol 33:563-606
Price, Aryn A; Sampson, Timothy R; Ratner, Hannah K et al. (2015) Cas9-mediated targeting of viral RNA in eukaryotic cells. Proc Natl Acad Sci U S A 112:6164-9

Showing the most recent 10 out of 375 publications