This research will be performed primarily in Quito, Ecuador, Universidad Central Del Ecuador, Facultad de Ciencias Medicas and Centro de Biomedicina in collaboration with Drs. Victor Espin and Edmundo Estevez, as an extension of NIH grant R01AI39499 (6/1/97-12/31/08 with no-cost extension). Chlamydia trachomatis (CT) is the leading cause of sexually transmitted diseases (STD) in the developed and developing world. CT infections and their sequelae of pelvic inflammatory disease, ectopic pregnancy, and infertility are responsible for ~80% of the estimated $4 billion annual cost of infections in the U.S. Also, ~50% of women are reinfected and, thus, are at increased risk for these sequelae. Many reinfections may reflect persistence, which likely plays an important role in pathogenesis. The major outer membrane protein (MOMP) and the gene that encodes MOMP, ompA, comprise important targets for typing CT. We have developed a finer typing system, multi-locus sequence typing (MLST), which will be combined with ompA genotyping to improve correlations with disease phenotypes. To date, MLST has been developed for 21 different human pathogens to discriminate colonization vs. invasive disease types. Also, since mutations in trpA have been associated with an inability of CT to synthesize tryptophan (required for replication) using exogenous substrates, which may result in persistence, we will also evaluate this gene for mutations and correlate these with CT genetic profiles and clinical findings. Further, because of a lack of understanding of the host-pathogen interaction in disease and the importance of inflammation in CT STDs, we will also screen the cohort for host genetic susceptibility to inflammation. This will enhance our understanding of the role of SNPs in disease and persistence.
Aim 1. Identify and analytically compare MLST and trpA and ompA profiles among CT isolates from the Ecuador population collected over time. Low-SES adolescents, young adults and female commercial sex workers will be followed prospectively every 3 months for prevalence and incidence rates of CT STDs over 2 years. Each sample that is CT positive by Amplicor PCR (Roche) will be cultured and subjected to ompA typing, trpA sequencing and MLST to define the CT genetic profile for each sample, which will be used to determine associations with clinical findings, demographics, reinfection, persistence, and with host SNPs (as described in Aim 2). We hypothesize that: 1) many recurrent infections actually represent persistent infection;and 2) unique CT genetic profiles are associated with persistence.
Aim 2. Determine wild-type and SNPs among genes associated with inflammation among the same Ecuador population. The population will undergo genetic typing for SNPs and wild-type among genes associated with inflammation. These data will be correlated with those in Aim 1 to determine whether specific SNPs and/or CT genetic profiles correlate with patient susceptibility to disease, reinfection or persistence. Hypothesis 3: specific SNPs in the patient are associated with persistent CT infections and disease.This FIRCA application will provide significant new data on the natural history of Chlamydia trachomatis (CT) sexually transmitted diseases (STD). CT is the leading bacterial cause of STDs worldwide, and we predict that many CT recurrence infections actually represent persistent infection, the knowledge of which will result in altering therapy and will support the development of screening tests to detect persistence. Genetic profiles of the organism (from urogenital samples from our patient population) that correlate with disease phenotypes such as persistence will allow for future studies using specific in vitro and in vivo models;we also predict that single nucleotide polymorphisms (SNP) in genes that encode proteins responsible for inflammation will be associated with persistence and disease among our patients, which will result in defining a new research area for the field of Chlamydia.
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