Persisting Mycobacterium tuberculosis (Mtb) evade rapid killing by chemotherapeutic agents and are the reservoir for treatment failure and relapse of tuberculosis (TB) treatment. To date, other than persistently positive cultures, no biomarkers have been identified that effectively predict which TB patients are at risk for treatment relapse after apparent cure. We will recruit a prospective cohort of patients undergoing treatment for MDR TB in Seoul, Korea, using a protocol in place for serial evaluations by [18F]-fiuoro-2-deoxy-Dglucose positron emission tomography/ computer tomography (FDG-PET/CT) during and after completion of therapy. The natural history of the post-treatment phase of TB disease will be investigated, with specific attention to identifying evidence of persistent organisms by FDG-PET/CT scan and defining biomarkers that predict PET/CT scan activity and clinical relapse. Candidate biomarkers include host transcriptome and proteome profiles, effector and memory T cell cells and polyfunctional T cells. These markers will be evaluated and correlated with treatment outcomes. The potential use of biomarker assays to monitor treatment response for MDR TB patients, whose therapy is more toxic and for whom second line drugs are less efficacious, would facilitate determination of more evidence-based treatment durations and provide an earlier endpoint for investigation of novel therapeutics.
Aim 1 will determine the association between abnormalities on FDG-PET/CT scan and relapse of TB patients after completion of treatment;
Aim 2 will develop and validate a model to predict Mtb persistence and treatment relapse of MDR TB patients based on changes in biomarkers;
Aim 3 will prospectively validate the most promising biomarkers as predictors of relapse in drug-susceptible TB. Identification of FDG-PET/CT scan abnormalities associated with persistent disease will provide important insights into the biology of mycobacterial persistence in humans and lead to optimal choice of potential biomarkers to evaluate as predictors of persistent disease.
TB treatment is long and a significant number of treated patients relapse. In this proposal we plan to identify markers that can tell whether a person is going to relapse way before they actually relapse.
|Koch, Anastasia S; Brites, Daniela; Stucki, David et al. (2017) The Influence of HIV on the Evolution of Mycobacterium tuberculosis. Mol Biol Evol 34:1654-1668|
|Tientcheu, Leopold D; Koch, Anastasia; Ndengane, Mthawelenga et al. (2017) Immunological consequences of strain variation within the Mycobacterium tuberculosis complex. Eur J Immunol 47:432-445|
|Saito, Kohta; Warrier, Thulasi; Somersan-Karakaya, Selin et al. (2017) Rifamycin action on RNA polymerase in antibiotic-tolerant Mycobacterium tuberculosis results in differentially detectable populations. Proc Natl Acad Sci U S A 114:E4832-E4840|
|Jones-López, Edward C; Acuña-Villaorduña, Carlos; Fregona, Geisa et al. (2017) Incident Mycobacterium tuberculosis infection in household contacts of infectious tuberculosis patients in Brazil. BMC Infect Dis 17:576|
|Esmail, Hanif; Wilkinson, Robert J (2017) Minimizing Tuberculosis Risk in Patients Receiving Anti-TNF Therapy. Ann Am Thorac Soc 14:621-623|
|Geadas, Carolina; Stoszek, Sonia K; Sherman, David et al. (2017) Advances in basic and translational tuberculosis research: Proceedings of the first meeting of RePORT international. Tuberculosis (Edinb) 102:55-67|
|Vilchèze, Catherine; Hartman, Travis; Weinrick, Brian et al. (2017) Enhanced respiration prevents drug tolerance and drug resistance in Mycobacterium tuberculosis. Proc Natl Acad Sci U S A 114:4495-4500|
|Yang, Jason H; Bening, Sarah C; Collins, James J (2017) Antibiotic efficacy-context matters. Curr Opin Microbiol 39:73-80|
|Prosser, Gareth; Brandenburg, Julius; Reiling, Norbert et al. (2017) The bacillary and macrophage response to hypoxia in tuberculosis and the consequences for T cell antigen recognition. Microbes Infect 19:177-192|
|Collins, Lauren F; Geadas, Carolina; Ellner, Jerrold J (2016) Diagnosis of Latent Tuberculosis Infection: Too Soon to Pull the Plug on the Tuberculin Skin Test. Ann Intern Med 164:122-4|
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