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. Despite many years of effort, the Chlamydia remain intractable to genetic analysis due to their obligate intracellular lifestyle and complex developmental cycle. Our long-term goal is to apply the full range of molecular tools including the power of genetics to study the pathogenic mechanisms and intracellular metabolism of Chlamydia.
The aims of this proposal include a technology development aim (genetic tools) and two hypothesis-driven aims to address significant questions of Chlamydia biology.
The specific aims are: 1 - Development of tools for the genetic analysis of Chlamydia. 2 - Biochemical and genetic characterization of peptidoglycan synthesis in Chlamydia. 3 - Identification of transport systems for uptake of essential constituents for Chlamydia growth. We will employ new and innovative approaches to build on our past success and develop genetic tools in aim 1. Success in achieving this aim will have a significant impact and advance the field of Chlamydia research by making new tools available for genetic analysis of Chlamydia.
Aim 2 will identify the enzymes involved in two key cytoplasmic steps in peptidoglycan (PG) synthesis and also apply new techniques to isolate and demonstrate the presence of PG components in Chlamydia. We will also screen for Chlamydia mutants defective in signaling to the host via PG fragments as a first step in dissecting the role of PG in host response. Success in aim 2 will finally resolve the """"""""Chlamydia anomaly"""""""" and reveal potential new targets for antimicrobial development.
Aim 3 will characterize transport systems used by Chlamydia to acquire iron and biotin from the host cytosol. Mechanisms of iron acquisition by Chlamydia are completely unknown and our innovative approach will use a Shigella mutant to screen a Chlamydia library. Since the genes for biotin synthesis are absent in C. trachomatis, transport of this essential vitamin is critical for growth. In both cases, success in this aim will shed light on processes of nutrient acquisition that are potential targets for therapeutic intervention. In broader terms, the significance of this aim is that it will provide insight into metabolic processes of obligate intracellular pathogens.

Public Health Relevance

Chlamydia cause severe genital, pulmonary, and ocular diseases with serious consequences, in particular for women's reproductive health. There are large gaps in our knowledge of the metabolism, physiology and pathogenesis of Chlamydia because of the lack of genetic tools. The aims of this project will lead to the development of genetic tools to study Chlamydia as well as lead to a better understanding of cell wall synthesis and transport of essential nutrients all of which can identify targets for effective prevention and treatment of Chlamydia infections.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1-IDM-S (03))
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Hiltke, Thomas J
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Henry M. Jackson Fdn for the Adv Mil/Med
United States
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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
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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

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