Abstract

This program is the continuation of a long-term study of the regulation of genes responsible for staphylococcal pathogenesis, collectively known as the virulon. The present application deals with the mechanism of function and interactions of two key signaling systems, agr and sae, on their relation other regulatory elements, and on their relation to clinical disease. It addresses the ways in which these two systems determine the specificities of in vitro and in vivo behavior - the lifestyles of the organism, Specific Aims are 1. To determine the mechanism by which agr-RNAIII regulates target gene expression. 2. To analyze the regulatory functions of the saeRS system and its interactions with agr. 3. To determine the in vivo functionality and interactions of these two regulatory systems.
In Aim 1, a variety of in vivo and in vitro techniques will be used to identify the intermediary transcription factors that are directly regulated by RNAIII, focusing on regulation of translation.
In Aim 2, gene fusions and deletions will be used to characterize the regulatory organization of the sae locus and its interaction with agr, and with other regulatory inputs.
In Aim 3, the function of selected regulatory genes in vitro will be compared with activities in vivo. Accomplishment of these objectives will not only enhance our basic scientific understanding of the interaction between a pathogenic organism and its host, but may also contribute to our ability to control the organism so as to treat or prevent infections.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI030138-19
Application #
7893059
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Huntley, Clayton C
Project Start
1991-09-01
Project End
2012-06-30
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
19
Fiscal Year
2010
Total Cost
$431,715
Indirect Cost

  Institution

Name
New York University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016

  Publications

Geisinger, Edward; Chen, John; Novick, Richard P (2012) Allele-dependent differences in quorum-sensing dynamics result in variant expression of virulence genes in Staphylococcus aureus. J Bacteriol 194:2854-64
Smyth, Davida S; Kafer, Jared M; Wasserman, Gregory A et al. (2012) Nasal carriage as a source of agr-defective Staphylococcus aureus bacteremia. J Infect Dis 206:1168-77
Shopsin, Bo; Eaton, Christian; Wasserman, Gregory A et al. (2010) Mutations in agr do not persist in natural populations of methicillin-resistant Staphylococcus aureus. J Infect Dis 202:1593-9
George Cisar, Elizabeth A; Geisinger, Edward; Muir, Tom W et al. (2009) Symmetric signalling within asymmetric dimers of the Staphylococcus aureus receptor histidine kinase AgrC. Mol Microbiol 74:44-57
Chen, John; Novick, Richard P (2007) svrA, a multi-drug exporter, does not control agr. Microbiology 153:1604-8
Adhikari, Rajan P; Arvidson, Staffan; Novick, Richard P (2007) A nonsense mutation in agrA accounts for the defect in agr expression and the avirulence of Staphylococcus aureus 8325-4 traP::kan. Infect Immun 75:4534-40
Geisinger, Edward; Adhikari, Rajan P; Jin, Ruzhong et al. (2006) Inhibition of rot translation by RNAIII, a key feature of agr function. Mol Microbiol 61:1038-48
Ji, Guangyong; Pei, Wuhong; Zhang, Linsheng et al. (2005) Staphylococcus intermedius produces a functional agr autoinducing peptide containing a cyclic lactone. J Bacteriol 187:3139-50
Weinrick, Brian; Dunman, Paul M; McAleese, Fionnuala et al. (2004) Effect of mild acid on gene expression in Staphylococcus aureus. J Bacteriol 186:8407-23
Charpentier, Emmanuelle; Anton, Ana I; Barry, Peter et al. (2004) Novel cassette-based shuttle vector system for gram-positive bacteria. Appl Environ Microbiol 70:6076-85

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