Bacteria of the genus Chlamydia are significant pathogens of animals and man. The diseases caused by Chlamydia spp. in man include pneumonia, endocarditis, polyarthritis, blindness, and a wide range of sexually transmitted diseases including cervicitis, salpingitis, pelvic inflammatory disease, and infertility in females;and non-gonococcal urethritis and acute epididymitis in males. Chlamydia has also been implicated as a cofactor in a variety of chronic diseases such as coronary heart disease. Despite many years of effort, the Chlamydia remain intractable to genetic analysis due to their obligate intracellular lifestyle and complex developmental cycle. No one has been able to introduce foreign DNA into this organism and achieve stable inheritance of and expression of the foreign genes. Our long-term goal is to apply the power of genetics to study the pathogenic mechanisms of Chlamydia.
The aims of this proposal include the development of genetic tools for the analysis of Chlamydia pathogenesis and hypothesis-driven aims to address specific questions of Chlamydia biology.
The specific aims are to: 1) develop a method for introduction, expression, and stable maintenance of foreign DNA in Chlamydia and a system for gene replacement in Chlamydia;2) characterize the pathway for peptidoglycan synthesis mChlamydia;and, 3) identify the transport system for uptake of essential constituents for Chlamydia growth, specifically the source of methyl donors for methyltransferases. We will employ genetic, biochemical and cell biology strategies to each aim. Success in achieving the first aim will have a significant impact on Chlamydia research by making new tools for genetic analysis of Chlamydia available. Rapid advances in our understanding of Chlamydia pathogenesis and biology as well as the ability to construct Chlamydia mutants for vaccine development will be made possible by these new techniques. Success in aim 2 will finally resolve the chlamydia anomaly while aim 3 will attempt to resolve another apparent paradox of Chlamydia biology. Thus, these two aims will resolve some long-standing questions of Chlamydia biology and extend our knowledge of the intracellular lifestyle of this important pathogen..

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI044033-10
Application #
7754422
Study Section
Bacterial Pathogenesis Study Section (BACP)
Program Officer
Hiltke, Thomas J
Project Start
1998-12-01
Project End
2012-09-17
Budget Start
2010-02-01
Budget End
2012-09-17
Support Year
10
Fiscal Year
2010
Total Cost
$285,737
Indirect Cost
Name
Henry M. Jackson Fdn for the Adv Mil/Med
Department
Type
DUNS #
144676566
City
Bethesda
State
MD
Country
United States
Zip Code
20817
Liechti, George; Singh, Raghuveer; Rossi, Patricia L et al. (2018) Chlamydia trachomatis dapF Encodes a Bifunctional Enzyme Capable of Both d-Glutamate Racemase and Diaminopimelate Epimerase Activities. MBio 9:
Liechti, George; Kuru, Erkin; Packiam, Mathanraj et al. (2016) Pathogenic Chlamydia Lack a Classical Sacculus but Synthesize a Narrow, Mid-cell Peptidoglycan Ring, Regulated by MreB, for Cell Division. PLoS Pathog 12:e1005590
Bliven, Kimberly A; Maurelli, Anthony T (2016) Evolution of Bacterial Pathogens Within the Human Host. Microbiol Spectr 4:
Fisher, Derek J; Adams, Nancy E; Maurelli, Anthony T (2015) Phosphoproteomic analysis of the Chlamydia caviae elementary body and reticulate body forms. Microbiology 161:1648-58
Liechti, G W; Kuru, E; Hall, E et al. (2014) A new metabolic cell-wall labelling method reveals peptidoglycan in Chlamydia trachomatis. Nature 506:507-10
Bliven, Kimberly A; Fisher, Derek J; Maurelli, Anthony T (2012) Characterization of the activity and expression of arginine decarboxylase in human and animal Chlamydia pathogens. FEMS Microbiol Lett 337:140-6
Fisher, Derek J; Fernández, Reinaldo E; Adams, Nancy E et al. (2012) Uptake of biotin by Chlamydia Spp. through the use of a bacterial transporter (BioY) and a host-cell transporter (SMVT). PLoS One 7:e46052
Binet, Rachel; Fernandez, Reinaldo E; Fisher, Derek J et al. (2011) Identification and characterization of the Chlamydia trachomatis L2 S-adenosylmethionine transporter. MBio 2:e00051-11
Binet, Rachel; Bowlin, Anne K; Maurelli, Anthony T et al. (2010) Impact of azithromycin resistance mutations on the virulence and fitness of Chlamydia caviae in guinea pigs. Antimicrob Agents Chemother 54:1094-101
Binet, Rachel; Maurelli, Anthony T (2009) The chlamydial functional homolog of KsgA confers kasugamycin sensitivity to Chlamydia trachomatis and impacts bacterial fitness. BMC Microbiol 9:279

Showing the most recent 10 out of 12 publications