Abstract

(Project 3, Vance) Intracellular pathogens remain a significant global cause of human morbidity and mortality. The overall goal of this Program Project Grant is to characterize the host pathways that specifically detect and eliminate intracellular bacterial pathogens. Project 3 will contribute to this overall goal by focusing on the intracellular gram-negative bacterial pathogen Legionella pneumophila, the cause of Legionnaires' Disease in humans. As in previous iterations of this Program Project Grant, our core strategy is to compare the host responses induced by L. pneumophila to those induced by L. monocytogenes (Project 1) and M. tuberculosis (Project 2). Leveraging these comparisons allows us to identify pathogen-specific responses as well as universal responses induced by diverse intracellular bacterial pathogens.
Three aims are proposed.
In Aim 1, we test the hypothesis that postranscriptional responses downstream of the STING pathway are important in controlling intracellular bacterial infections.
In Aim 2, we test the hypothesis that L. pneumophila specifically targets the mTORC1 pathway. We hypothesize that mTORC1 manipulation liberates host amino acids for bacterial consumption, but also contributes to innate immune responses to the bacterium. Lastly, in Aim 3, we take a broader approach and use comprehensive profiling technologies to identify novel post-transcriptional responses that regulate the host response to L. pneumophila. Our expectation is that by discovering novel host pathways that regulate intracellular bacterial growth and innate immunity, we will identify targets that can be exploited for therapeutic intervention.

Public Health Relevance

(Project 3, Vance) Legionella pneumophila is an intracellular bacterium that causes Legionnaires' Disease in humans, and is an excellent model organism for the study of immune responses to infection. In this project, we seek to determine the fundamental mechanisms by which host cells detect and eliminate L. pneumophila, with the expectation that our studies will identify novel therapeutic targets for the treatment of bacterial infection.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI063302-17
Application #
9977107
Study Section
Special Emphasis Panel (ZAI1)
Project Start
2004-12-01
Project End
2021-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
17
Fiscal Year
2020
Total Cost
Indirect Cost

  Institution

Name
University of California Berkeley
Department
Type
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94710

  Publications

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
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
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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