The incidence of infectious syphilis has doubled in the United States since 2000, and has increased dramatically in Western Europe and in China during that time. In addition to serious clinical sequelae in adults, congenital syphilis is responsible for a high proportion of fetal and neonatal morbidity and mortality in developing countries. Syphilis is a chronic sexually transmitted infection which, untreated, lasts for many decades. When our laboratory discovered sequence variation in seven discrete regions (termed V regions) of TprK, a putative surface- exposed protein of Treponema pallidum, we hypothesized that this represents an antigenic variation system, leading to immune evasion and contributing to the chronic nature of syphilis infection. Syphilis is transmissible by sexual contact only during the early (primary and secondary) stages, however, so what is the evolutionary advantage of decades-long persistence? Antigenic variation must impart another advantage to the bacterium. We now hypothesize that the major advantage of TprK antigenic variation by T. pallidum lies in the prolongation of the infectious stages: longer duration of the primary chancre, immune escape to permit development of secondary lesions, and longer duration of secondary lesions. Immune clearance of T. pallidum from early lesions occurs via phagocytosis of opsonized T. pallidum by activated macrophages, so organisms persisting in these lesions must be able to evade this immune activity to delay lesion resolution. This is consistent with our earlier finding that treponemes persisting in lesions following initial immune clearance in vivo are resistant to opsonophagocytosis. In this renewal application, we propose to focus on the early stages of syphilis infection in the rabbit model and to define, at the molecular and functional level, the role of TprK V region variation in immune escape. Specifically, we propose the following aims: 1) Define the mechanism(s) by which specific anti-TprK antibodies contribute to the clearance of T. pallidum from healing primary lesions;2) Identify the epitopes recognized by functional anti- TprK antibodies;3) Determine whether new variants comprise the treponemes seen in secondary lesions;4) Investigate whether variant-specific antibodies are induced by new variant TprK antigens;and 5) Determine the role of interferon-3 in development of new TprK variants. These studies will elucidate the mechanisms by which TprK antigenic variation contributes to immune evasion by T. pallidum and leads to long duration of the infectious stages of syphilis.

Public Health Relevance

Syphilis is an important and common disease. This grant application will study how the bacterium that causes syphilis, Treponema pallidum, evades the immune response of the infected host to prolong the period of infectivity. We will study a protein called TprK that is thought to be exposed on the surface of the bacterial cell. TprK undergoes changes in its sequence which inhibits the ability of antibodies to bind it, thus enabling the bacterium to escape from host immunity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI063940-09
Application #
8288879
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Hiltke, Thomas J
Project Start
2004-07-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
9
Fiscal Year
2012
Total Cost
$348,555
Indirect Cost
$124,919
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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Cameron, Caroline E; Lukehart, Sheila A (2014) Current status of syphilis vaccine development: need, challenges, prospects. Vaccine 32:1602-9
Giacani, Lorenzo; Lukehart, Sheila A (2014) The endemic treponematoses. Clin Microbiol Rev 27:89-115
Lukehart, Sheila A; Giacani, Lorenzo (2014) When is syphilis not syphilis? Or is it? Sex Transm Dis 41:554-5
Centurion-Lara, Arturo; Giacani, Lorenzo; Godornes, Charmie et al. (2013) Fine analysis of genetic diversity of the tpr gene family among treponemal species, subspecies and strains. PLoS Negl Trop Dis 7:e2222
Ho, Emily L; Lukehart, Sheila A (2011) Syphilis: using modern approaches to understand an old disease. J Clin Invest 121:4584-92
Marra, Christina M; Sahi, Sharon K; Tantalo, Lauren C et al. (2010) Enhanced molecular typing of treponema pallidum: geographical distribution of strain types and association with neurosyphilis. J Infect Dis 202:1380-8
Giacani, Lorenzo; Jeffrey, Brendan M; Molini, Barbara J et al. (2010) Complete genome sequence and annotation of the Treponema pallidum subsp. pallidum Chicago strain. J Bacteriol 192:2645-6
Giacani, Lorenzo; Molini, Barbara J; Kim, Eric Y et al. (2010) Antigenic variation in Treponema pallidum: TprK sequence diversity accumulates in response to immune pressure during experimental syphilis. J Immunol 184:3822-9
Deitsch, Kirk W; Lukehart, Sheila A; Stringer, James R (2009) Common strategies for antigenic variation by bacterial, fungal and protozoan pathogens. Nat Rev Microbiol 7:493-503

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