Syphilis remains a public health threat worldwide, with an estimated 12 million new infections per year and a global burden of 25 million infections. Within the last decade there has been an increase in syphilis outbreaks in major cities around the world, with a 10-fold increase in syphilis infections documented for China and Canada and a doubling of syphilis infections in the United States. Syphilis infections increase the risk of acquiring and transmitting HIV, and there has been a 23% increase in congenital syphilis infections, resulting from mother to child transmission in utero, in recent years within the United States. Although syphilis is curable with penicillin treatment if diagnosed early, the worldwide syphilis prevalence shows that elimination of this disease will not occur through public health control measures alone, and instead will require development of an effective syphilis vaccine. Development of a syphilis vaccine requires an in depth knowledge of the pathogenic mechanisms used by this highly successful pathogen. The bacterium that causes syphilis, Treponema pallidum, is able to disseminate rapidly within the host during the early stages of infection to infect every organ and tissue. The pathogenic mechanisms used by T. pallidum to undergo widespread dissemination throughout the host are not known, and gaining understanding within this highly relevant area of study will reveal novel vaccine candidates that can be targeted to prevent establishment of infection. The long-term objective of the research project is to elucidate the mechanisms that facilitate attachment of T. pallidum to host components and widespread treponemal dissemination and, specifically, to determine the role of two T. pallidum proteases, pallilysin and Tp0750, in this important pathogenic process. To accomplish this objective, the following specific aims are proposed: (1) to elucidate the mechanism of host component attachment and proteolysis for pallilysin and Tp0750;(2) to determine the ability of these two proteases to exploit the host fibrinolytic process that is essential for normal host component degradation and turnover;(3) to use sensitive proteomic methodologies and a "model" treponeme to determine the location of these two proteases within T. pallidum;and (4) to directly determine the role these two proteases play in dissemination of T. pallidum. These studies will increase understanding of the critical process of T. pallidum dissemination and will reveal suitable vaccine candidates for prevention of syphilis infection.

Public Health Relevance

Syphilis infections continue to be prevalent worldwide, with an estimated global burden of 25 million cases and recent outbreaks observed in North America, Europe and Asia. The bacterium that causes syphilis is one of the most invasive organisms known, and this research investigates how the bacterium is able to spread so widely and rapidly within the host. This research will identify proteins that can be used to develop a vaccine to prevent syphilis infections.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01AI051334-11
Application #
8616711
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Hiltke, Thomas J
Project Start
Project End
Budget Start
Budget End
Support Year
11
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Victoria
Department
Type
DUNS #
City
Victoria
State
BC
Country
Canada
Zip Code
V8 5C2
Parker, Michelle L; Houston, Simon; Wetherell, Charmaine et al. (2016) The Structure of Treponema pallidum Tp0624 Reveals a Modular Assembly of Divergently Functionalized and Previously Uncharacterized Domains. PLoS One 11:e0166274
Champredon, D; Cameron, C E; Smieja, M et al. (2016) Epidemiological impact of a syphilis vaccine: a simulation study. Epidemiol Infect 144:3244-3252
Houston, Simon; Taylor, John S; Denchev, Yavor et al. (2015) Conservation of the Host-Interacting Proteins Tp0750 and Pallilysin among Treponemes and Restriction of Proteolytic Capacity to Treponema pallidum. Infect Immun 83:4204-16
Cameron, Caroline E; Lukehart, Sheila A (2014) Current status of syphilis vaccine development: need, challenges, prospects. Vaccine 32:1602-9
Houston, Simon; Russell, Shannon; Hof, Rebecca et al. (2014) The multifunctional role of the pallilysin-associated Treponema pallidum protein, Tp0750, in promoting fibrinolysis and extracellular matrix component degradation. Mol Microbiol 91:618-34
Smith, Brenden C; Simpson, Yvonne; Morshed, Muhammad G et al. (2013) New proteins for a new perspective on syphilis diagnosis. J Clin Microbiol 51:105-11
Dickerson, Matthew T; Abney, Morgan B; Cameron, Caroline E et al. (2012) Fibronectin binding to the Treponema pallidum adhesin protein fragment rTp0483 on functionalized self-assembled monolayers. Bioconjug Chem 23:184-95
Houston, Simon; Hof, Rebecca; Honeyman, Lisa et al. (2012) Activation and proteolytic activity of the Treponema pallidum metalloprotease, pallilysin. PLoS Pathog 8:e1002822
Desrosiers, Daniel C; Anand, Arvind; Luthra, Amit et al. (2011) TP0326, a Treponema pallidum β-barrel assembly machinery A (BamA) orthologue and rare outer membrane protein. Mol Microbiol 80:1496-515
Houston, Simon; Hof, Rebecca; Francescutti, Teresa et al. (2011) Bifunctional role of the Treponema pallidum extracellular matrix binding adhesin Tp0751. Infect Immun 79:1386-98

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