Abstract

Francisella tularensis is a highly infectious gram-negative coccobacillus that causes the zoonosis tularemia and is a Category A agent. F. tularensis survives and replicates within macrophages, a phenotype that correlates with virulence, yet little is understood about the molecular basis of its pathogenesis. The long-term goal of this project is to understand how F. tularensis subverts host defenses.
This aim will fundamentally interface with the goal of this Program Project, which is to understand how diverse intracellular pathogens such as Mycobacterium tuberculosis, Listeria monocytogenes and Histoplasma capsulatum manipulate host innate responses. We hypothesize that a comparative analysis of the macrophage transcriptional responses to these four intracellular pathogens will be a very powerful means of dissecting and understanding the results of our microarray experiments. We hypothesize that F. tularensis produces gene products that alter the trafficking and perhaps acidification of the initial bacterial phagosome, thereby allowing bacteria to escape into the cytoplasm where it can survive and replicate. The objective of this proposal is to use molecular genetic approaches to uncover F. tularensis molecules that are required for intracellular survival and growth. In a parallel approach, DNA microarrays will be used to characterize the macrophage response to F. tularensis and to test our hypothesis that this pathogen will induce a cytosolic pathway of host gene expression similar to L. monocytogenes.
Our specific aims are to 1) identify F. tularensis genes that are expressed inside of macrophages and construct mutants defective in macrophage replication; 2) analyze the intracellular replication and trafficking of F. tularensis; and 3) characterize the macrophage transcriptional response to F. tularensis. These studies will identify regulatory circuits in host cells that are manipulated by F. tularensis and other key intracellular pathogens relevant to biodefense.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI063302-03
Application #
7188968
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2006-02-01
Budget End
2007-01-31
Support Year
3
Fiscal Year
2006
Total Cost
$441,244
Indirect Cost

  Institution

Name
University of California Berkeley
Department
Type
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704

  Publications

Cheng, Mandy I; Chen, Chen; Engström, Patrik et al. (2018) Actin-based motility allows Listeria monocytogenes to avoid autophagy in the macrophage cytosol. Cell Microbiol 20:e12854
Mitchell, Gabriel; Cheng, Mandy I; Chen, Chen et al. (2018) Listeria monocytogenes triggers noncanonical autophagy upon phagocytosis, but avoids subsequent growth-restricting xenophagy. Proc Natl Acad Sci U S A 115:E210-E217
Penn, Bennett H; Netter, Zoe; Johnson, Jeffrey R et al. (2018) An Mtb-Human Protein-Protein Interaction Map Identifies a Switch between Host Antiviral and Antibacterial Responses. Mol Cell 71:637-648.e5
Chen, Chen; Nguyen, Brittney N; Mitchell, Gabriel et al. (2018) The Listeriolysin O PEST-like Sequence Co-opts AP-2-Mediated Endocytosis to Prevent Plasma Membrane Damage during Listeria Infection. Cell Host Microbe 23:786-795.e5
Nguyen, Brittney N; Peterson, Bret N; Portnoy, Daniel A (2018) Listeriolysin O: a phagosome-specific cytolysin revisited. Cell Microbiol :e12988
Price, Jordan V; Jiang, Kallie; Galantowicz, Abigail et al. (2018) Legionella pneumophila Is Directly Sensitive to 2-Deoxyglucose-Phosphate via Its UhpC Transporter but Is Indifferent to Shifts in Host Cell Glycolytic Metabolism. J Bacteriol 200:
Light, Samuel H; Su, Lin; Rivera-Lugo, Rafael et al. (2018) A flavin-based extracellular electron transfer mechanism in diverse Gram-positive bacteria. Nature 562:140-144
Deng, Weiwen; Lira, Victor; Hudson, Thomas E et al. (2018) Recombinant Listeria promotes tumor rejection by CD8+ T cell-dependent remodeling of the tumor microenvironment. Proc Natl Acad Sci U S A 115:8179-8184
Price, April E; Shamardani, Kiarash; Lugo, Kyler A et al. (2018) A Map of Toll-like Receptor Expression in the Intestinal Epithelium Reveals Distinct Spatial, Cell Type-Specific, and Temporal Patterns. Immunity 49:560-575.e6
Whiteley, Aaron T; Ruhland, Brittany R; Edrozo, Mauna B et al. (2017) A Redox-Responsive Transcription Factor Is Critical for Pathogenesis and Aerobic Growth of Listeria monocytogenes. Infect Immun 85:

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