Investigation of immunity and latency to chlamydial infection links host immune responses with chlamydial growth modulation. The concept that chlamydial infections progress to chronic disease has been acknowledged for decades in animals, but is supported by only meager data in humans. Cell culture models do provide proof of principle for the chronic infection (latency) hypothesis. The most compelling mechanistic model is referred to as chlamydial persistence and involves induction of non-productive, but reversible, intracellular chlamydial growth elicited by Th1 immune regulated cytokines (e.g. gamma interferon; IFN-g) on chlamydial host cells. This model has been developed in a variety of human cell culture systems and is based on the induction of an enzyme (indoleamine 2,3-dioxygenase, IDO) that decyclizes tryptophan, creating a nutrient deficient intracellular environment to restrict intracellular chlamydial growth. Study of persistence has, however, been hampered in vivo because appropriate animal models are not available. A major reason for this deficit is that although the mouse is a convenient model for C. trachomatis genital tract disease, murine IFN-g-mediated responses are different from responses observed in humans. Murine immune responses to chlamydiae in wild type animals are likely to result in eradicative immunity rather than persistence, although the full repertoire of lethal and static mouse responses are not yet fully elucidated. Therefore, to gain a better appreciation of requirements for development of chronic chlamydial infections in mice the murine antimicrobial activities elicited by IFN-g will be systematically classified in cell culture (e.g. iNOS, arginase, p47, phox, IDO) using several cell types and primary cells from conventional and knock out mice. Cell culture results will be exploited to study mice that are genetically manipulated or chemically treated to elicit responses that provide an environment conducive to development of chronic chlamydial genital tract infection. Results will provide an improved tractable model of chlamydial persistence, furnish a way to understand more completely the pathogenesis of chronic chlamydial infections, and help define requirements for efficacious vaccine design.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI019782-22
Application #
7387353
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Hiltke, Thomas J
Project Start
1982-08-01
Project End
2011-03-31
Budget Start
2008-04-01
Budget End
2009-03-31
Support Year
22
Fiscal Year
2008
Total Cost
$344,697
Indirect Cost
Name
University of Tennessee Health Science Center
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
941884009
City
Memphis
State
TN
Country
United States
Zip Code
38163
Grayston, J Thomas; Belland, Robert J; Byrne, Gerald I et al. (2015) Infection with Chlamydia pneumoniae as a cause of coronary heart disease: the hypothesis is still untested. Pathog Dis 73:1-9
Peters, Jan; Byrne, Gerald I (2015) Chlamydia trachomatis growth depends on eukaryotic cholesterol esterification and is affected by Acyl-CoA:cholesterol acyltransferase inhibition. Pathog Dis 73:ftv028
Patil, Renukadevi; Szabó, Erzsébet; Fells, James I et al. (2015) Combined mitigation of the gastrointestinal and hematopoietic acute radiation syndromes by an LPA2 receptor-specific nonlipid agonist. Chem Biol 22:206-16
Bonner, Carol A; Byrne, Gerald I; Jensen, Roy A (2014) Chlamydia exploit the mammalian tryptophan-depletion defense strategy as a counter-defensive cue to trigger a survival state of persistence. Front Cell Infect Microbiol 4:17
Bavoil, Patrik M; Byrne, Gerald I (2014) Analysis of CPAF mutants: new functions, new questions (the ins and outs of a chlamydial protease). Pathog Dis 71:287-91
Jonsson, Colleen B; Cole, Kelly Stefano; Roy, Chad J et al. (2013) Challenges and Practices in Building and Implementing Biosafety and Biosecurity Programs to Enable Basic and Translational Research with Select Agents. J Bioterror Biodef Suppl 3:12634
Abdelsamed, Hossam; Peters, Jan; Byrne, Gerald I (2013) Genetic variation in Chlamydia trachomatis and their hosts: impact on disease severity and tissue tropism. Future Microbiol 8:1129-1146
Miyairi, Isao; Ziebarth, Jesse; Laxton, Jonathan D et al. (2012) Host genetics and Chlamydia disease: prediction and validation of disease severity mechanisms. PLoS One 7:e33781
Ziebarth, Jesse D; Bhattacharya, Anindya; Chen, Anlong et al. (2012) PolymiRTS Database 2.0: linking polymorphisms in microRNA target sites with human diseases and complex traits. Nucleic Acids Res 40:D216-21
Peters, Jan; Onguri, Vijaya; Nishimoto, Satoru K et al. (2012) The Chlamydia trachomatis CT149 protein exhibits esterase activity in vitro and catalyzes cholesteryl ester hydrolysis when expressed in HeLa cells. Microbes Infect 14:1196-204

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