Syphilis is a significant problem for global health. It is caused by Treponema pallidum subsp. pallidum (T. palidum), a highly virulent, invasive and intractable spirochete. The goal of this proposal is to use comparative genomics on a population-wide scale to determine the contribution of genetic mutations to the identification of T. pallidum strains associated with distinct tissue enrichments, to the development of a refined strain fingerprinting method and for genome-wide expression profiling. Comparative genome-wide analysis will be done on a number of T. pallidum isolates as well as more recent isolates originated from patients with distinct clinical presentations and diverse geographical distributions.
The Specific Aims are as follows: 1. Determine the population genomic variability of T. pallidum isolates representing geographical and chronological diversity;2. Identify repeated mutational changes (hot spot mutations) in T. pallidum. High-throughput de novo, state-of-the-art sequencing approaches will be used to obtain a comprehensive number of genome sequences from our collection of T. pallidum isolates. We will create a publicly available database that will include a genome-wide map of mutations acquired in T. pallidum. Targeted qRT-PCR analysis will be performed to determine impact of hot spots on transcript levels of selected genes. Overall, accomplishment of the proposed studies will set the basis for the advance of our understanding at the molecular level of the epidemiology of T. pallidum isolates. It will also lay the groundwork for futures studies on a large scale, population-wide association research between specific genetic variations and tissue/organ/system involvement, and for a better understanding at the molecular level of how treponemes can, for example, re-infect or super-infect individuals. These studies can have a far reaching impact on issues of clinical and public health significance.

Public Health Relevance

Understanding the mechanisms Treponema pallidum uses to cause different clinical presentations and how this organism can re-infect or super-infect an individual will have a significant impact on public health. Furthermore, the studies will help to understand the epidemiology of syphilis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI094126-01A1
Application #
8303036
Study Section
Special Emphasis Panel (ZRG1-IDM-A (80))
Program Officer
Hiltke, Thomas J
Project Start
2012-03-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
1
Fiscal Year
2012
Total Cost
$192,916
Indirect Cost
$67,916
Name
University of Washington
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Lukehart, Sheila A; Giacani, Lorenzo (2014) When is syphilis not syphilis? Or is it? Sex Transm Dis 41:554-5