For bacterial pathogens, the first studies that begin to define the microorganism?s functional genetic nature on a genome-wide scale, frequently represent a landmark and highly impactful achievement. The major human pathogen, Chlamydia trachomatis, is a bacterium for which such studies have not been performed, in large part due to Chlamydia?s obligate intracellular nature and historical intractability to modern genetic perturbations. With the development of two major genetic tools for Chlamydia by our group?transposon mutagenesis and conditional temperature-sensitive mutants?functional genomic investigations in Chlamydia are now possible. Our long term goal is to globally define and functionally characterize the genetic correlates to C. trachomatis infection and pathogenesis. Using the new approaches described above, we propose to: (i) build defined mutant libraries of transposon and temperature-sensitive conditional mutants in model Chlamydia strains, (ii) screen these libraries for hallmark in vitro and in vivo growth defects using a clinically relevant murine genital tract model, and (iii) determine the Chlamydia genes associated with host adaptation by exploiting interspecies lateral gene transfer for Chlamydia and the inability of human parental strains to infect mice. These efforts are essential for gaining a functional appreciation of the role chlamydial genes play in the organism?s growth and development, and also Chlamydia?s evolutionary adaptation to successfully maintain infection and pathogenesis in complex mammalian hosts. We anticipate that Chlamydia will serve as a model obligate intracellular bacterium, and, therefore, the knowledge obtained from this work will broadly extend to other pathogens that have similarly evolved an obligate intracellular niche in their mammalian hosts. Identification of these loci is critical for our understanding the mechanism of Chlamydia adaptation to mammalian hosts, and is an important step towards elucidating the major virulence correlates of C. trachomatis in humans.

Public Health Relevance

Chlamydia trachomatis is the leading cause of sexually transmitted infection and elicits a major burden on reproductive health throughout the world. This project will globally define, for the first time, the Chlamydia genes that are critical for mediating this bacterium?s ability to infect cells and establish acute and severe infections in a murine female genital tract infection model. The knowledge to be gained from these efforts will open up numerous new avenues of investigation for the field focused on determining the molecular function of proteins encoded by the essential genes we will define.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI126785-03
Application #
9469476
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Vincent, Leah Rebecca
Project Start
2016-05-15
Project End
2021-04-30
Budget Start
2018-05-01
Budget End
2019-04-30
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195