Bacteria of the genus Yersinia are responsible for a variety of human diseases. Y. pestis causes the infamous disease Plague, which has regained prominence in public awareness due to its potential use as an agent of bioterrorism. In contrast, Y. pseudotuberculosis and Y. enterocolitica cause primarily gastrointestinal disease. However, despite the differences in disease symptoms, these three 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 a specialized 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 its virulence. Our studies on the Psp system to date have identified its core components and begun to define their roles. We will base our future work on the hypotheses that regulation of the Y. enterocolitica Psp system is mediated by complex and dynamic protein- protein interactions, and that the activated system functions to counter problems associated with the cytoplasmic membrane, such as can be caused by a mislocalized secretin. To address these hypotheses we propose to: (1) Test various models of how the PspFABC proteins may constitute a signal transduction system that regulates psp gene expression via dynamic protein-protein interactions;(2) Analyze the regulatory and physiological functions of the PspB and PspC proteins, which play multiple essential roles in the system;(3) Directly analyze the connections between secretin toxicity, secretin mislocalization to the cytoplasmic membrane, and the function of the Psp system in Y. enterocolitica. These studies also have broad significance beyond Y. enterocolitica because secretin-containing systems critical for virulence, and the Psp system, are widespread in medically important bacteria. Therefore, by understanding the Psp system we will gain further insight into the essential ability of bacteria to respond to stressful conditions that occur during host infection.

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 stress-response system in Y. enterocolitica that is essential for its ability to cause disease, and is also present in numerous other medically important bacteria. 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 #
5R01AI052148-10
Application #
8418767
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Alexander, William A
Project Start
2002-07-01
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2015-01-31
Support Year
10
Fiscal Year
2013
Total Cost
$425,634
Indirect Cost
$174,393
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
Darwin, Andrew J (2013) Stress relief during host infection: The phage shock protein response supports bacterial virulence in various ways. PLoS Pathog 9:e1003388
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
Yamaguchi, Saori; Darwin, Andrew J (2012) Recent findings about the Yersinia enterocolitica phage shock protein response. J Microbiol 50:1-7
Gueguen, Erwan; Flores-Kim, Josue; Darwin, Andrew J (2011) The Yersinia enterocolitica phage shock proteins B and C can form homodimers and heterodimers in vivo with the possibility of close association between multiple domains. J Bacteriol 193:5747-58
Singh, Sindhoora; Darwin, Andrew J (2011) FtsH-dependent degradation of phage shock protein C in Yersinia enterocolitica and Escherichia coli. J Bacteriol 193:6436-42
Yamaguchi, Saori; Gueguen, Erwan; Horstman, N Kaye et al. (2010) Membrane association of PspA depends on activation of the phage-shock-protein response in Yersinia enterocolitica. Mol Microbiol 78:429-43
Gueguen, Erwan; Savitzky, Diana C; Darwin, Andrew J (2009) Analysis of the Yersinia enterocolitica PspBC proteins defines functional domains, essential amino acids and new roles within the phage-shock-protein response. Mol Microbiol 74:619-33
Seo, Jin; Savitzky, Diana C; Ford, Emily et al. (2007) Global analysis of tolerance to secretin-induced stress in Yersinia enterocolitica suggests that the phage-shock-protein system may be a remarkably self-contained stress response. Mol Microbiol 65:714-27
Darwin, Andrew J (2007) Regulation of the phage-shock-protein stress response in Yersinia enterocolitica. Adv Exp Med Biol 603:167-77
Maxson, Michelle E; Darwin, Andrew J (2006) PspB and PspC of Yersinia enterocolitica are dual function proteins: regulators and effectors of the phage-shock-protein response. Mol Microbiol 59:1610-23

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