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)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI051334-10A1
Application #
8505064
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Hiltke, Thomas J
Project Start
2002-04-15
Project End
2018-01-31
Budget Start
2013-02-15
Budget End
2014-01-31
Support Year
10
Fiscal Year
2013
Total Cost
$239,286
Indirect Cost
$17,725
Name
University of Victoria
Department
Type
DUNS #
209567957
City
Victoria
State
BC
Country
Canada
Zip Code
V8 5-C2
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
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
Desrosiers, Daniel C; Anand, Arvind; Luthra, Amit et al. (2011) TP0326, a Treponema pallidum ?-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
Cameron, Caroline E; Kuroiwa, Janelle M Y; Yamada, Mitsunori et al. (2008) Heterologous expression of the Treponema pallidum laminin-binding adhesin Tp0751 in the culturable spirochete Treponema phagedenis. J Bacteriol 190:2565-71
Cullen, Paul A; Cameron, Caroline E (2006) Progress towards an effective syphilis vaccine: the past, present and future. Expert Rev Vaccines 5:67-80
Cameron, Caroline E; Brouwer, Nathan L; Tisch, Lisa M et al. (2005) Defining the interaction of the Treponema pallidum adhesin Tp0751 with laminin. Infect Immun 73:7485-94
Cameron, Caroline E; Brown, Elizabeth L; Kuroiwa, Janelle M Y et al. (2004) Treponema pallidum fibronectin-binding proteins. J Bacteriol 186:7019-22
Van Voorhis, Wesley C; Barrett, Lynn K; Lukehart, Sheila A et al. (2003) Serodiagnosis of syphilis: antibodies to recombinant Tp0453, Tp92, and Gpd proteins are sensitive and specific indicators of infection by Treponema pallidum. J Clin Microbiol 41:3668-74

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