Chlamydia trachomatis(CT) is the leading cause of sexually transmitted diseases (STD) in the developed world. CT infections and their sequelae of pelvic inflammatory disease, ectopic pregnancy, and infertility are responsible for approximately 80% of the estimated $2.5 billion annual cost of these infections in the United States. Further, up to 50% of women become reinfected and are at increased risk for these sequelae. Many reinfections reflect persistence that likely plays an important role in pathogenesis. The major outer membrane protein is considered to be the immunodominant protein of CT. However, the discovery of open reading frames predicted to encode a nine-member polymorphic membrane protein (Prop) gene (pmp) family in the recently published genome sequence of CT serovar D suggest that these Props may also be important in chlamydial biology. Further, CT contains a partial tryptophan biosynthesis operon (trpR, trpA, trpB) not found in a CT mouse strain (MoPn) or other species of Chlamydia. Tryptophan is essential for chlamydial replication, and tryptophan depletion in vitro results in chlamydial persistence. Our hypothesis is that the prop and tryptophan genes may undergo selection that results in differential expression or activity of these proteins that: 1) consequently determine active or persistent infection; and 2) are significantly involved in pathogenesis as an outcome of persistence or outcome of other factors. By analyzing the genetic profile of prototype and serial recurrent and persistent CT STD patient strains and by correlating these data with epidemiologic and clinical findings, we hope to identify the genes, genetic/protein variation and evolution of this variation in the organism, and how these are linked to persistence and pathogenesis. Thus, this grant will answer broad questions about the genetic and protein basis for persistence and for pathogenesis, and provide important research tools including a Database and DNA microarray that will be of long-term benefit to investigators in the field of Chlamydia.
The Specific Aims for this grant are to: 1) Sequence the nine pmps, and trpR, trpA, and trpB genes for the 19 prototype serovars of CT and create a DNA microarray for these genes and ompA to differentiate strains of CT, and for use in Aim 2; and 2) Identify polymorphisms in and protein expression of the nine props, specific tryptophan operon genes, and other constitutively expressed genes among serial cervical samples from patients with persistent versus non-persistent CT STDs; correlate the genetic and protein expression profiles of these serial samples with epidemiologic and clinical findings.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI039499-06A2
Application #
6573304
Study Section
Bacteriology and Mycology Subcommittee 2 (BM)
Program Officer
Quackenbush, Robert L
Project Start
2003-09-15
Project End
2007-12-31
Budget Start
2003-09-15
Budget End
2003-12-31
Support Year
6
Fiscal Year
2003
Total Cost
$93,391
Indirect Cost
Name
Children's Hospital & Res Ctr at Oakland
Department
Type
DUNS #
076536184
City
Oakland
State
CA
Country
United States
Zip Code
94609
Sharma, Manu; Recuero-Checa, Maria A; Fan, Frances Yue et al. (2018) Chlamydia trachomatis regulates growth and development in response to host cell fatty acid availability in the absence of lipid droplets. Cell Microbiol 20:
Somboonna, Naraporn; Wan, Raymond; Ojcius, David M et al. (2011) Hypervirulent Chlamydia trachomatis clinical strain is a recombinant between lymphogranuloma venereum (L(2)) and D lineages. MBio 2:e00045-11
Atik, Berna; Johnston, S Claiborne; Dean, Deborah (2010) Association of carotid plaque Lp-PLA(2) with macrophages and Chlamydia pneumoniae infection among patients at risk for stroke. PLoS One 5:e11026
Dean, Deborah; Bruno, William J; Wan, Raymond et al. (2009) Predicting phenotype and emerging strains among Chlamydia trachomatis infections. Emerg Infect Dis 15:1385-94
Tan, Chun; Hsia, Ru-ching; Shou, Huizhong et al. (2009) Chlamydia trachomatis-infected patients display variable antibody profiles against the nine-member polymorphic membrane protein family. Infect Immun 77:3218-26
Somboonna, Naraporn; Mead, Sally; Liu, Jessica et al. (2008) Discovering and differentiating new and emerging clonal populations of Chlamydia trachomatis with a novel shotgun cell culture harvest assay. Emerg Infect Dis 14:445-53
Skwor, Troy A; Atik, Berna; Kandel, Raj Prasad et al. (2008) Role of secreted conjunctival mucosal cytokine and chemokine proteins in different stages of trachomatous disease. PLoS Negl Trop Dis 2:e264
Nunes, Alexandra; Gomes, Joao P; Mead, Sally et al. (2007) Comparative expression profiling of the Chlamydia trachomatis pmp gene family for clinical and reference strains. PLoS One 2:e878
Gomes, Joao P; Bruno, William J; Nunes, Alexandra et al. (2007) Evolution of Chlamydia trachomatis diversity occurs by widespread interstrain recombination involving hotspots. Genome Res 17:50-60
Gomes, Joao P; Borrego, Maria J; Atik, Berna et al. (2006) Correlating Chlamydia trachomatis infectious load with urogenital ecological success and disease pathogenesis. Microbes Infect 8:16-26

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