The expression of virulence determinants is tightly regulated so that they are produced at the right place and for the correct time during infection of an animal or plant host. The master regulator of Salmonella pathogenicity is the PhoP/PhoQ system, which consists of the sensor for extracytoplasmic Mg2+ PhoQ and the DNA binding transcriptional regulator PhoP. We have determined that PhoP-dependent genes can be differentially expressed in response to additional signals, which are often detected by the leader regions of PhoP-dependent mRNAs. This proposal describes experiments that explore: first, the identity of the signals detected by the leader sequence of the mgtCBR operon, which encodes proteins involved in Mg2+ homeostasis and virulence;second, the mechanisms by which the leader sequences of the mgtA and mgtCBR genes control expression of the corresponding coding regions;and third, novel PhoP-dependent genes that are regulated after the initiation of gene transcription step. An accomplishment of these goals will take us closer to understanding the mechanisms by which a microbe can modify its gene expression program in response to environmental cues as well as intracellular signals. Our project addresses the defining character that distinguishes bacteria and archeae from organisms that possess a nucleus: the coupling of transcription and translation. Therefore, it is anticipated that our findings will provide valuable insight into gene regulation in other bacterial species and by other regulatory systems.

Public Health Relevance

Bacterial pathogens exert tight control over their virulence determinants. This proposal examines how this control is mediated by the leader region of certain mRNAs, which can respond to a variety of chemical and physical signals by modifying whether the corresponding coding regions are expressed.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI049561-21
Application #
8220733
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Alexander, William A
Project Start
1992-04-01
Project End
2016-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
21
Fiscal Year
2012
Total Cost
$414,479
Indirect Cost
$164,479
Name
Yale University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Kriner, Michelle A; Sevostyanova, Anastasia; Groisman, Eduardo A (2016) Learning from the Leaders: Gene Regulation by the Transcription Termination Factor Rho. Trends Biochem Sci 41:690-9
Kriner, Michelle A; Groisman, Eduardo A (2015) The Bacterial Transcription Termination Factor Rho Coordinates Mg(2+) Homeostasis with Translational Signals. J Mol Biol 427:3834-49
Pontes, Mauricio H; Lee, Eun-Jin; Choi, Jeongjoon et al. (2015) Salmonella promotes virulence by repressing cellulose production. Proc Natl Acad Sci U S A 112:5183-8
Sevostyanova, Anastasia; Groisman, Eduardo A (2015) An RNA motif advances transcription by preventing Rho-dependent termination. Proc Natl Acad Sci U S A 112:E6835-43
Pontes, Mauricio H; Sevostyanova, Anastasia; Groisman, Eduardo A (2015) When Too Much ATP Is Bad for Protein Synthesis. J Mol Biol 427:2586-94
Park, Sun-Yang; Pontes, Mauricio H; Groisman, Eduardo A (2015) Flagella-independent surface motility in Salmonella enterica serovar Typhimurium. Proc Natl Acad Sci U S A 112:1850-5
Hollands, Kerry; Sevostiyanova, Anastasia; Groisman, Eduardo A (2014) Unusually long-lived pause required for regulation of a Rho-dependent transcription terminator. Proc Natl Acad Sci U S A 111:E1999-2007
Lee, Eun-Jin; Choi, Jeongjoon; Groisman, Eduardo A (2014) Control of a Salmonella virulence operon by proline-charged tRNA(Pro). Proc Natl Acad Sci U S A 111:3140-5
Zwir, Igor; Yeo, Won-Sik; Shin, Dongwoo et al. (2014) Bacterial nucleoid-associated protein uncouples transcription levels from transcription timing. MBio 5:e01485-14
Park, Sun-Yang; Groisman, Eduardo A (2014) Signal-specific temporal response by the Salmonella PhoP/PhoQ regulatory system. Mol Microbiol 91:135-44

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