Chlamydia are human pathogens that cause sterility, blindness, pneumonia and are strongly correlated with the number one cause of death in humans, heart disease. Chlamydia are obligate intracellular bacteria and are perpetuated through a defining biphasic developmental cycle that is intimately linked with pathogenesis. The developmental cycle is governed predominately at the transcriptional level;however, there is a critical deficiency in our understanding of developmental regulatory mechanisms in Chlamydia. The long-term goal in our research is to contribute to a delineation of the key molecular mechanisms that function to regulate chlamydial development and pathogenesis. The research we propose here is designed to define the biological role and essential regulatory mechanisms for the chlamydial transcription factor termed ChxR. ChxR is an atypical member of the OmpR subfamily of response regulators. Our central hypothesis is that ChxR has an important role in regulating middle and late stage gene expression and incorporates a mechanisms similar to, but distinct from, the subfamily of OmpR/PhoB response regulators. Largely due to the current genetic intractability of Chlamydia, the biological role of ChxR is not known. To elucidate the biological role and determine regulatory mechanism of ChxR the following specific aims are proposed: 1) define the direct gene targets of ChxR in vivo, 2) delineate the mechanism integral for chxR transcriptional activation, and 3) determine the intra- and inter- molecular interactions integral to ChxR function. As a result of these studies, we expect to address a fundamental question in the field, 'how do Chlamydia regulate their growth?'Furthermore, OmpR response regulators, like ChxR, are widespread in bacteria and absent in mammals. As such, they are attractive targets for the development of new antimicrobials. Characterization of the molecular mechanisms employed by ChxR for proper function will allow in the future for rationale design of novel molecules that interrupt the function of ChxR and Chlamydia infections.

Public Health Relevance

Proposed studies will facilitate our understanding of how and what controls the growth of and disease by the medically important bacteria, Chlamydia. The focus of this research is a protein that regulates factors that cause disease. What will be learned from this study will allow for future development of new antibiotics to disrupt the ability of Chlamydia to cause disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI079083-05
Application #
8648976
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Hiltke, Thomas J
Project Start
2010-05-01
Project End
2015-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Kansas Lawrence
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
City
Lawrence
State
KS
Country
United States
Zip Code
66045
Tifrea, Delia F; Barta, Michael L; Pal, Sukumar et al. (2016) Computational modeling of TC0583 as a putative component of the Chlamydia muridarum V-type ATP synthase complex and assessment of its protective capabilities as a vaccine antigen. Microbes Infect 18:245-53
Kemege, Kyle E; Hickey, John M; Barta, Michael L et al. (2015) Chlamydia trachomatis protein CT009 is a structural and functional homolog to the key morphogenesis component RodZ and interacts with division septal plane localized MreB. Mol Microbiol 95:365-82
Barta, Michael L; Battaile, Kevin P; Lovell, Scott et al. (2015) Hypothetical protein CT398 (CdsZ) interacts with σ(54) (RpoN)-holoenzyme and the type III secretion export apparatus in Chlamydia trachomatis. Protein Sci 24:1617-32
Barta, Michael L; Thomas, Keisha; Yuan, Hongling et al. (2014) Structural and biochemical characterization of Chlamydia trachomatis hypothetical protein CT263 supports that menaquinone synthesis occurs through the futalosine pathway. J Biol Chem 289:32214-29
Barta, Michael L; Lovell, Scott; Sinclair, Amy N et al. (2014) Chlamydia trachomatis CT771 (nudH) is an asymmetric Ap4A hydrolase. Biochemistry 53:214-24
Barta, Michael L; Hickey, John M; Anbanandam, Asokan et al. (2014) Atypical response regulator ChxR from Chlamydia trachomatis is structurally poised for DNA binding. PLoS One 9:e91760
Koppolu, Veerendra; Osaka, Ichie; Skredenske, Jeff M et al. (2013) Small-molecule inhibitor of the Shigella flexneri master virulence regulator VirF. Infect Immun 81:4220-31
Barta, Michael L; Hickey, John; Kemege, Kyle E et al. (2013) Structure of CT584 from Chlamydia trachomatis refined to 3.05 Å resolution. Acta Crystallogr Sect F Struct Biol Cryst Commun 69:1196-201
Hickey, John M; Weldon, Lindsey; Hefty, P Scott (2011) The atypical OmpR/PhoB response regulator ChxR from Chlamydia trachomatis forms homodimers in vivo and binds a direct repeat of nucleotide sequences. J Bacteriol 193:389-98
Hickey, John M; Lovell, Scott; Battaile, Kevin P et al. (2011) The atypical response regulator protein ChxR has structural characteristics and dimer interface interactions that are unique within the OmpR/PhoB subfamily. J Biol Chem 286:32606-16

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