: Listeria monocytogenes is a facultative, intra-cytoplasmic bacterial pathogen that is responsible for serious infections in immunocompromised patients, pregnant women, and neonates. L. monocytogenes infections are primarily food-borne and listeriosis is the leading cause of death from food-related illness. In addition to its significance as a human pathogen, L. monocytogenes also serves as a useful model system for exploring the intracellular interactions that take place between parasite and host. L. monocytogenes is capable of sensing the different host cell compartment environments it encounters during the course of infection and of responding with the regulated expression of virulence factors. The PrfA protein of L. monocytogenes is a key transcriptional activator of virulence gene expression. PrfA contributes to the temporal regulation of L. monocytogenes gene expression within host cells, but the mechanisms used by the bacterium to coordinate intracellular gene expression are unknown. The goal of these studies is to elucidate the mechanisms that govern intracellular gene expression and to identify L. monocytogenes gene products that are subject to this intracellular regulatory network.
In Aim 1, experiments are designed to analyze the mutations in L. monocytogenes regulatory mutants with altered patterns of intracellular gene expression and to define the effects of these mutations on virulence gene regulation. These studies should lead to the identification of new components that may act in concert with PrfA and that contribute to intracellular regulation of gene expression.
Aim 2 will define functional regions of PrfA that promote activation of virulence gene expression. The contributions of specific functional domains of PrfA to virulence gene regulation in L. monocytogenes will be assessed.
In Aim 3, studies are designed to identify additional L. monocytogenes gene products whose expression or activity is PrfA-dependent, and assess the contributions of these products to bacterial pathogenesis. The proposed studies should further our understanding as to how an intracellular bacterium senses the environment of different host cell compartments and regulates expression and activity of its virulence factors in response. This information is important towards better definition of the interactions that occur between host and pathogen during the process of infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI041816-11
Application #
6882686
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Program Officer
Hall, Robert H
Project Start
1997-02-01
Project End
2006-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
11
Fiscal Year
2005
Total Cost
$465,148
Indirect Cost
Name
Seattle Biomedical Research Institute
Department
Type
DUNS #
070967955
City
Seattle
State
WA
Country
United States
Zip Code
98109
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McMullen, P David; Freitag, Nancy E (2015) Assessing bacterial invasion of cardiac cells in culture and heart colonization in infected mice using Listeria monocytogenes. J Vis Exp :e52497
Sheridan, Brian S; Romagnoli, Pablo A; Pham, Quynh-Mai et al. (2013) ?? T cells exhibit multifunctional and protective memory in intestinal tissues. Immunity 39:184-95
Xayarath, Bobbi; Freitag, Nancy E (2012) Optimizing the balance between host and environmental survival skills: lessons learned from Listeria monocytogenes. Future Microbiol 7:839-52
McMullen, P David; Gillaspy, Allison F; Gipson, Jenny et al. (2012) Genome sequence of Listeria monocytogenes 07PF0776, a cardiotropic serovar 4b strain. J Bacteriol 194:3552
Xayarath, Bobbi; Smart, Jennifer I; Mueller, Kimberly J et al. (2011) A novel C-terminal mutation resulting in constitutive activation of the Listeria monocytogenes central virulence regulatory factor PrfA. Microbiology 157:3138-49
Xayarath, Bobbi; Volz, Karl W; Smart, Jennifer I et al. (2011) Probing the role of protein surface charge in the activation of PrfA, the central regulator of Listeria monocytogenes pathogenesis. PLoS One 6:e23502
Alonzo 3rd, Francis; Xayarath, Bobbi; Whisstock, James C et al. (2011) Functional analysis of the Listeria monocytogenes secretion chaperone PrsA2 and its multiple contributions to bacterial virulence. Mol Microbiol 80:1530-48
Alonzo 3rd, Francis; McMullen, P David; Freitag, Nancy E (2011) Actin polymerization drives septation of Listeria monocytogenes namA hydrolase mutants, demonstrating host correction of a bacterial defect. Infect Immun 79:1458-70
Alonzo 3rd, Francis; Bobo, Linda D; Skiest, Daniel J et al. (2011) Evidence for subpopulations of Listeria monocytogenes with enhanced invasion of cardiac cells. J Med Microbiol 60:423-34

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