The intracellular bacterium Chlamydia trachomatis is a major cause of sexually transmitted diseases and infectious blindness worldwide. The survival of Chlamydia in host cells largely relies on two fundamental processes 1) protecting its infectious intracellular compartment (so-called inclusion) from lysosomal killing and 2) hijacking host compartments to acquire lipids and material necessary for inclusion growth. Furthermore, C. trachomatis induces the homotypic fusion of its inclusions to promote its infectivity. To execute these events, C. trachomatis has evolved to be extraordinarily efficient at manipulating host vesicular trafficking and membrane fusion. Despite the importance of this intimate connection between host and Chlamydia, very little is known regarding the impact of this bacterium on the host membrane fusion machinery, the so-called SNAREs. In particular, it is not known whether Chlamydia extensively interferes with SNAREs to control host vesicular trafficking and promote its survival inside the cell. Using an innovative multidisciplinary approach, we will determine whether C. trachomatis (i) uses a series of SNARE-like proteins to specifically block endocytic/lysosomal host SNARE complexes and protect its inclusion from destruction and (ii) uses host SNAREs involved in the secretory pathway to induce fusion with host vesicles and promote the homotypic fusion of its inclusions. Ultimately, this information will guide the development of novel therapeutics that interfere with the establishment of the inclusion. Furthermore, the detailed characterization of chlamydial SNARE-like proteins will give scientists the fundamental tools to screen for their presence in other major human pathogens, including Salmonella typhi, and Mycobacterium tuberculosis, thus opening new avenues of research in infectious diseases.

Public Health Relevance

Infections caused by Chlamydia trachomatis are one of the most prevalent bacterial sexually transmitted diseases, and the world leading cause of infectious blindness. Identifying how Chlamydia manipulates the host cell to establish a successful intracellular lifestyle is critical to understanding the pathogenicity of this bacterium Furthermore, characterizing the mechanism used by Chlamydia to co-opt host vesicular trafficking will provide unique therapeutic opportunities.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI116983-03
Application #
9204786
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Hiltke, Thomas J
Project Start
2015-02-01
Project End
2020-01-31
Budget Start
2017-02-01
Budget End
2018-01-31
Support Year
3
Fiscal Year
2017
Total Cost
$390,000
Indirect Cost
$140,000
Name
Thomas Jefferson University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Wesolowski, Jordan; Weber, Mary M; Nawrotek, Agata et al. (2017) Chlamydia Hijacks ARF GTPases To Coordinate Microtubule Posttranslational Modifications and Golgi Complex Positioning. MBio 8:
Weber, Mary M; Noriea, Nicholas F; Bauler, Laura D et al. (2016) A Functional Core of IncA Is Required for Chlamydia trachomatis Inclusion Fusion. J Bacteriol 198:1347-55