Chlamydia trachomatis is the cause for the most common bacterial sexually transmitted disease in the United States. Commonly referred to as a silent epidemic, C. trachomatis infections in women are frequently asymptomatic, and often go unnoticed and untreated. The infection can persist for years and chronic infections ultimately result in pelvic inflammatory disease, ectopic pregnancies, and infertility. Whereas some individuals clear infections with C. trachomatis successfully, others fail to do so. The heterogeneity in the ability of individuals to clear C. trachomatis infections suggests a genetic component underlying the relative resistance to C. trachomatis infections. Our previous unbiased genetic approach led to the identification of Immunity Related GTPase (IRGs) as critical mediators of host resistance to C. trachomatis infections in mice. IRGM proteins, a subfamily of IRGs, exist both in mice and humans and human IRGM can provide resistance to C. trachomatis infections. Importantly, the human IRGM locus is highly polymorphic and has been associated with increased susceptibility to infectious and autoinflammatory diseases. Therefore, the IRGM locus is a strong candidate to be a critical determinant in shaping the outcome of C. trachomatis infections. We are pursuing three interrelated aims to understand how IRGM proteins provide resistance to C. trachomatis infections in mice and humans. (1) We will determine how IRGM proteins orchestrate cell-autonomous resistance pathways targeting C. trachomatis (2) We will define which human IRGM isoforms are responsible for providing resistance to C. trachomatis and whether genetic variants of the human IRGM gene differ in their ability to provide cell-autonomous resistance to C. trachomatis. (3) We will describe IRGM-dependent immune response to C. trachomatis in vivo using novel mouse models. It is hoped that these studies will not only substantially advance our understanding of host responses to C. trachomatis but also facilitate the development of novel immunological and pharmacological strategies to prevent chronic infections with C. trachomatis. !

Public Health Relevance

Human individuals differ dramatically in their ability to clear infections with the most common sexually transmitted bacterial pathogen, Chlamydia trachomatis, one of the leading causes for pelvic inflammatory disease and infertility in women. The immune mechanisms that distinguish a successful from a failed host response to Chlamydia are unknown. This application focuses on understanding how a cell-signaling molecule called Interferon-gamma instructs infected cells to restrict growth of Chlamydia through the action of highly variable gene named IRGM. Our findings will have implications for the design of Chlamydia vaccines and novel therapeutic strategies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI103197-01A1
Application #
8578032
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Hiltke, Thomas J
Project Start
2013-05-15
Project End
2018-04-30
Budget Start
2013-05-15
Budget End
2014-04-30
Support Year
1
Fiscal Year
2013
Total Cost
$368,950
Indirect Cost
$133,950
Name
Duke University
Department
Genetics
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Haldar, Arun K; Piro, Anthony S; Pilla, Danielle M et al. (2014) The E2-like conjugation enzyme Atg3 promotes binding of IRG and Gbp proteins to Chlamydia- and Toxoplasma-containing vacuoles and host resistance. PLoS One 9:e86684
Pilla, Danielle M; Hagar, Jon A; Haldar, Arun K et al. (2014) Guanylate binding proteins promote caspase-11-dependent pyroptosis in response to cytoplasmic LPS. Proc Natl Acad Sci U S A 111:6046-51
Coers, Jorn (2013) Self and non-self discrimination of intracellular membranes by the innate immune system. PLoS Pathog 9:e1003538