Bacteria of the genus Yersinia are responsible for a variety of human diseases. Y. pestis causes the infamous disease Plague, which regained prominence due to its potential use by bioterrorists. In contrast, Y. pseudotuberculosis and Y. enterocolitica cause primarily gastrointestinal disease. However, despite the differences in disease symptoms, these pathogenic Yersinia species are closely related and share several common virulence determinants. Yersinia studies have provided fundamental insights into bacterial pathogenesis, including the first example of the widespread type three secretion system (T3SS). A critical component of all T3SSs is an outer membrane pore-forming protein known as a secretin. However, secretin production can cause bacterial cell envelope stress. This is lethal to Y. enterocolitica unless a critical stress response known as the phage shock protein (Psp) system is functional. As a result, the Psp system of Y. enterocolitica is essential for virulence. Furthermore, the Psp system is also important for virulence and additional health-related processes in other bacteria. Our studies of the Psp system have identified its core components and defined their roles in regulation and stress tolerance. Some of our future work will focus on the two critical aspects of the Psp system required for Ye virulence: how is it activated and how is T3SS-induced cell death prevented? We have also identified a highly conserved gene (YE0566) that can both activate psp gene expression and suppress secretin-sensitivity in a psp null strain. This gene might direct the production of a 53 amino acid cytoplasmic membrane protein when cells are growing rapidly or an RpoS- induced non-coding RNA when cells enter stationary phase. We want to understand how YE0566 induces the Psp system and how it suppresses secretin-sensitivity when the Psp system is absent. To address all of our goals we propose to: (1) Investigate how an inducing signal is detected and transduced by the Psp system;(2) Analyze how the PspB and PspC proteins prevent secretins from permeabilizing the cytoplasmic membrane;(3) Investigate the regulation and function of YE0566. These studies also have broad significance beyond Y. enterocolitica because secretin-containing systems critical for virulence, the Psp system, and YE0566 homologues are widespread in medically important bacteria.

Public Health Relevance

The bacterium Yersinia enterocolitica causes human gastroenteritis and is closely related to the causative agent of Plague, Y. pestis. The proposed research will increase our understanding of a highly conserved stress- response system that is essential for virulence and other health-related processes in Y. enterocolitica and in other pathogens. Understanding this stress-response system is vital, because in the long-term it could be a target for the design of new therapeutic strategies against Yersinia species as well as other disease-causing bacteria.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI052148-11
Application #
8695130
Study Section
Special Emphasis Panel (ZRG1-IDM-T (02))
Program Officer
Alexander, William A
Project Start
2002-07-01
Project End
2018-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
11
Fiscal Year
2014
Total Cost
$399,596
Indirect Cost
$163,846
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
Flores-Kim, Josué; Darwin, Andrew J (2016) The Phage Shock Protein Response. Annu Rev Microbiol 70:83-101
Flores-Kim, Josué; Darwin, Andrew J (2015) Activity of a bacterial cell envelope stress response is controlled by the interaction of a protein binding domain with different partners. J Biol Chem 290:11417-30
Rau, Reina; Darwin, Andrew J (2015) Identification of YsaP, the Pilotin of the Yersinia enterocolitica Ysa Type III Secretion System. J Bacteriol 197:2770-9
Flores-Kim, Josué; Darwin, Andrew J (2014) Regulation of bacterial virulence gene expression by cell envelope stress responses. Virulence 5:835-51
Yamaguchi, Saori; Reid, Dylan A; Rothenberg, Eli et al. (2013) Changes in Psp protein binding partners, localization and behaviour upon activation of the Yersinia enterocolitica phage shock protein response. Mol Microbiol 87:656-71
Darwin, Andrew J (2013) Stress relief during host infection: The phage shock protein response supports bacterial virulence in various ways. PLoS Pathog 9:e1003388
Flores-Kim, Josue; Darwin, Andrew J (2012) Phage shock protein C (PspC) of Yersinia enterocolitica is a polytopic membrane protein with implications for regulation of the Psp stress response. J Bacteriol 194:6548-59
Flores-Kim, Josue; Darwin, Andrew J (2012) Links between type III secretion and extracytoplasmic stress responses in Yersinia. Front Cell Infect Microbiol 2:125
Horstman, N Kaye; Darwin, Andrew J (2012) Phage shock proteins B and C prevent lethal cytoplasmic membrane permeability in Yersinia enterocolitica. Mol Microbiol 85:445-60
Yamaguchi, Saori; Darwin, Andrew J (2012) Recent findings about the Yersinia enterocolitica phage shock protein response. J Microbiol 50:1-7

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