This application is a competitive renewal of a Program Project Grant entitled, "Intracellular pathogens and innate immunity," originally funded in 2004 and renewed in 2009 with two years of funding from the ARRA. The central problem under investigation is how intracellular pathogens are recognized by the host innate immune system and conversely, how pathogens avoid and/or manipulate the host response to promote their pathogenesis. The program consists of three projects and two cores. In Project 1, Portnoy proposes to extend his discovery that L. monocytogenes activates a host cytosolic surveillance pathway (CSP) leading to the expression of IFN-? and co-regulated genes. During the past funding period, the bacterial ligand was identified as c-di-AMP, a newly discovered small bacterial signaling molecule that appears to be essential for bacterial growth, and is secreted through a bacterial multidrug efflux pump. The role of c-di-AMP during infection and immunity will be explored. In Project 2, Cox found that M. tuberculosis requires the ESX-1 auxiliary secretion system to activate the CSP, and he proposes to identify and characterize the bacterial ligand(s) and host factors that contribute to the response. In Project 3, Vance collaborates with the other two groups and focuses on the identification and characterization of host factors that control the CSP. He has already established a program of ENU mutagenesis and identified that the host protein Sting is necessary for the response to L. monocytogenes, M. tuberculosis, c-di-AMP, c-di-GMP, and DNA. Furthermore, in preliminary data, Sting appears to be the cyclic-di-nucleotide receptor. Core B, managed by Barton, is a mouse and ENU core that will continue to generate and breed approximately 25 strains of mice with single, double and triple mutations in relevant innate immune pathways. The core will also manage the ENU forward genetic screen and dispense potential mutant macrophages to the other project leaders to screen for host defects in innate immune pathways. The purpose of Core A is to ensure scientific progress and promote synergy by providing scientific, organizational, and administrative leadership, which will be accomplished by extensive review of scientific progress during monthly meetings of all the lab groups.

Public Health Relevance

The proposed studies will lead to the characterization of a host system of innate immunity that will lead to vaccines and/or therapeutics to treat disease, with relevance to biodefense, emerging infections, and global health.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI063302-11
Application #
8700299
Study Section
Special Emphasis Panel (ZAI1-QV-I (M3))
Program Officer
Miller, Lara R
Project Start
2004-12-01
Project End
2016-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
11
Fiscal Year
2014
Total Cost
$1,907,421
Indirect Cost
$491,745
Name
University of California Berkeley
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704
Koch, Meghan A; Reiner, Gabrielle L; Lugo, Kyler A et al. (2016) Maternal IgG and IgA Antibodies Dampen Mucosal T Helper Cell Responses in Early Life. Cell 165:827-41
Burke, Thomas P; Portnoy, Daniel A (2016) SpoVG Is a Conserved RNA-Binding Protein That Regulates Listeria monocytogenes Lysozyme Resistance, Virulence, and Swarming Motility. MBio 7:e00240
Newman, Zachary R; Young, Janet M; Ingolia, Nicholas T et al. (2016) Differences in codon bias and GC content contribute to the balanced expression of TLR7 and TLR9. Proc Natl Acad Sci U S A 113:E1362-71
Mitchell, Gabriel; Chen, Chen; Portnoy, Daniel A (2016) Strategies Used by Bacteria to Grow in Macrophages. Microbiol Spectr 4:
Sanman, Laura E; Qian, Yu; Eisele, Nicholas A et al. (2016) Disruption of glycolytic flux is a signal for inflammasome signaling and pyroptotic cell death. Elife 5:e13663
Rauch, Isabella; Tenthorey, Jeannette L; Nichols, Randilea D et al. (2016) NAIP proteins are required for cytosolic detection of specific bacterial ligands in vivo. J Exp Med 213:657-65
Mitchell, Gabriel; Ge, Liang; Huang, Qiongying et al. (2015) Avoidance of autophagy mediated by PlcA or ActA is required for Listeria monocytogenes growth in macrophages. Infect Immun 83:2175-84
Coady, Alison; Sil, Anita (2015) MyD88-dependent signaling drives host survival and early cytokine production during Histoplasma capsulatum infection. Infect Immun 83:1265-75
McKay, Susannah L; Portnoy, Daniel A (2015) Ribosome hibernation facilitates tolerance of stationary-phase bacteria to aminoglycosides. Antimicrob Agents Chemother 59:6992-9
Siegrist, M Sloan; Aditham, Arjun K; Espaillat, Akbar et al. (2015) Host actin polymerization tunes the cell division cycle of an intracellular pathogen. Cell Rep 11:499-507

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