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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Special Emphasis Panel (ZRG1-IDM-T (02))
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Alexander, William A
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New York University
Schools of Medicine
New York
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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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