Chlamydia trachomatis is the leading cause of preventable blindness in developing countries and the most commonly reported sexually transmitted infection worldwide. Chlamydia pneumoniae is the cause of approximately 10% of community-acquired respiratory infections worldwide. C. trachomatis and C. pneumoniae have been implicated in more serious disease sequelae that have been proposed to arise due to chronic inflammatory conditions associated with persistent infections. The cytokine IFN-? plays a central role in controlling chlamydial infections and has been shown to induce a persistent growth state in cell culture models. Persistent growth in the presence of IFN-? has been shown to block the normal developmental cycle of the organisms and prevent the differentiation of the organism to the infectious form. We plan to study the role of a family of non-coding RNAs in the developmental cycle and the changes associated with IFN- ?- induced persistent growth. The hypothesis to be tested is that ncRNAs play an important role in the developmental cycle and are centrally involved in the changes associated with persistent growth in the presence of IFN-?. Non-coding RNAs will be identified using intergenic and genome-wide tiling microarrays and will be confirmed by Northern analysis and transcript mapping procedures. The mechanism of action of the confirmed non-coding RNAs will be studied using co-expression studies in Escherichia coli. Finally, the regulatory roles of non-coding RNAs will be tested during normal and IFN-?-induced persistent growth of C. trachomatis and C. pneumoniae using microarray analysis, quantitative gene expression analysis and combined gene expression and protein expression studies. The proposed work will result in a more complete understanding of the developmental cycle of C. trachomatis and C. pneumoniae and will lead to a mechanistic understanding of the chlamydial response to the human innate immune-response. Regulatory RNAs represent a new class of targets for non-traditional antibacterials in a rapidly developing field of study. Narrative: The pathogenic chlamydiae are responsible for respiratory disease, sexually transmitted disease, blinding trachoma and associated chronic diseases. This project uses genome level analyses to determine the role of a new class of RNA regulators in normal growth and the response of the bacteria to the host's immune system. These regulators control important aspects of the bacteria's response to its environment and their role in normal and chronic forms of infection will be studied.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI070693-05
Application #
8197066
Study Section
Host Interactions with Bacterial Pathogens Study Section (HIBP)
Program Officer
Hiltke, Thomas J
Project Start
2007-12-15
Project End
2013-11-30
Budget Start
2011-12-01
Budget End
2013-11-30
Support Year
5
Fiscal Year
2012
Total Cost
$357,737
Indirect Cost
$112,712
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
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Yao, Jiangwei; Abdelrahman, Yasser M; Robertson, Rosanna M et al. (2014) Type II fatty acid synthesis is essential for the replication of Chlamydia trachomatis. J Biol Chem 289:22365-76
Aiyar, Ashok; Quayle, Alison J; Buckner, Lyndsey R et al. (2014) Influence of the tryptophan-indole-IFN? axis on human genital Chlamydia trachomatis infection: role of vaginal co-infections. Front Cell Infect Microbiol 4:72
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Cox, John V; Naher, Nirun; Abdelrahman, Yasser M et al. (2012) Host HDL biogenesis machinery is recruited to the inclusion of Chlamydia trachomatis-infected cells and regulates chlamydial growth. Cell Microbiol 14:1497-512
Abdelrahman, Yasser M; Rose, Lorne A; Belland, Robert J (2011) Developmental expression of non-coding RNAs in Chlamydia trachomatis during normal and persistent growth. Nucleic Acids Res 39:1843-54
O'Connell, Catherine M; AbdelRahman, Yasser M; Green, Erin et al. (2011) Toll-like receptor 2 activation by Chlamydia trachomatis is plasmid dependent, and plasmid-responsive chromosomal loci are coordinately regulated in response to glucose limitation by C. trachomatis but not by C. muridarum. Infect Immun 79:1044-56