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 #
5R01AI051334-11
Application #
8616711
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
2014-02-01
Budget End
2015-01-31
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
Houston, Simon; Lithgow, Karen Vivien; Osbak, Kara Krista et al. (2018) Functional insights from proteome-wide structural modeling of Treponema pallidum subspecies pallidum, the causative agent of syphilis. BMC Struct Biol 18:7
Cameron, Caroline E (2018) Syphilis Vaccine Development: Requirements, Challenges, and Opportunities. Sex Transm Dis 45:S17-S19
Rekart, Michael L; Ndifon, Wilfred; Brunham, Robert C et al. (2017) A double-edged sword: does highly active antiretroviral therapy contribute to syphilis incidence by impairing immunity to Treponema pallidum? Sex Transm Infect 93:374-378
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Kao, Wei-Chien Andrew; P?trošová, Helena; Ebady, Rhodaba et al. (2017) Identification of Tp0751 (Pallilysin) as a Treponema pallidum Vascular Adhesin by Heterologous Expression in the Lyme disease Spirochete. Sci Rep 7:1538
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Parker, Michelle L; Houston, Simon; P?trošová, Helena et al. (2016) The Structure of Treponema pallidum Tp0751 (Pallilysin) Reveals a Non-canonical Lipocalin Fold That Mediates Adhesion to Extracellular Matrix Components and Interactions with Host Cells. PLoS Pathog 12:e1005919
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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

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