Chlamydia trachomatis is the most widespread sexually transmitted bacterial pathogen in the world. People infected with C. trachomatis are often initially asymptomatic, hindering the proper diagnostic and therapeutic strategies necessary to impede this ?silent epidemic?. If not properly treated, the bacteria are able to establish a long-lasting, persistent infection that can ultimately lead to severe medical sequelae. These complications arise predominantly in women, and include pelvic inflammatory disease, life-threatening ectopic pregnancies or infertility. A critical component of the microbial pathogenesis of C. trachomatis is its ability to evade immune detection and other antimicrobial responses conferred by its human host. These host defenses are largely galvanized by the cytokine interferon-gamma (IFN?), which stimulates epithelial cells occupying the site of an infection to up regulate the expression of interferon-stimulated-genes (ISGs). These ISGs are then responsible for the execution and immune clearance of invading microbes. In order to subvert the effects of IFN? and successfully replicate in epithelial cells, C. trachomatis must have evolved counterdefenses to ISGs that normally target and destroy other bacterial pathogens. However, the identity and function of these ISGs, as well as the C. trachomatis virulence effectors that inhibit ISG functions, are poorly understood. In pursuit of answering these questions, we performed two complementary screens to identify i) ISGs with anti-Chlamydia activities and ii) C. trachomatis genetic mutants with hypersensitivity to IFN? treatment.
In Aim 1 of this proposal, we will use a combination of functional genetics and cell biological studies in human cells to dissect the intracellular responses conferred by these anti-Chlamydia ISGs.
In Aim 2, we will combine parallel approaches in bacterial genetics and whole-genome sequencing to pinpoint the causative genetic elements responsible for C. trachomatis evasion of IFN?-mediated immunity. Taken together, these experiments will interrogate the dynamic relationship between cell-intrinsic defenses mediated by human ISGs and counter- resistance mechanisms of Chlamydia that are employed during infection. Implications of these studies will provide important platforms for the development of novel anti-Chlamydia medicines or vaccination strategies that treat its associated disease.

Public Health Relevance

This project seeks to examine the host-pathogen interactions that underlie Chlamydia trachomatis pathogenesis in human cells. We will examine a branch of human innate immunity that targets intracellular microbial pathogens, as well as the co-evolved C. trachomatis genetic traits that specifically circumvent these cellular defense circuits. The completion of this project will have important translational implications in the development of improved prophylactics and therapeutics against the emerging epidemic caused by C. trachomatis infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31AI150106-02
Application #
10124046
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Vincent, Leah Rebecca
Project Start
2020-03-01
Project End
2023-02-28
Budget Start
2021-03-01
Budget End
2022-02-28
Support Year
2
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Duke University
Department
Genetics
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705