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 #
5R01AI049561-22
Application #
8444552
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Alexander, William A
Project Start
1992-04-01
Project End
2016-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
22
Fiscal Year
2013
Total Cost
$390,785
Indirect Cost
$155,785
Name
Yale University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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
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
Park, Sun-Yang; Groisman, Eduardo A (2014) Signal-specific temporal response by the Salmonella?PhoP/PhoQ regulatory system. Mol Microbiol 91:135-44
Lee, Eun-Jin; Pontes, Mauricio H; Groisman, Eduardo A (2013) A bacterial virulence protein promotes pathogenicity by inhibiting the bacterium's own F1Fo ATP synthase. Cell 154:146-56
Yeo, Won-Sik; Zwir, Igor; Huang, Henry V et al. (2012) Intrinsic negative feedback governs activation surge in two-component regulatory systems. Mol Cell 45:409-21
Hollands, Kerry; Proshkin, Sergey; Sklyarova, Svetlana et al. (2012) Riboswitch control of Rho-dependent transcription termination. Proc Natl Acad Sci U S A 109:5376-81
Zwir, Igor; Latifi, Tammy; Perez, J Christian et al. (2012) The promoter architectural landscape of the Salmonella PhoP regulon. Mol Microbiol 84:463-85
Raghavan, Rahul; Groisman, Eduardo A; Ochman, Howard (2011) Genome-wide detection of novel regulatory RNAs in E. coli. Genome Res 21:1487-97
Jarvik, Tyler; Smillie, Chris; Groisman, Eduardo A et al. (2010) Short-term signatures of evolutionary change in the Salmonella enterica serovar typhimurium 14028 genome. J Bacteriol 192:560-7

Showing the most recent 10 out of 42 publications