OF THE OVERALL U19 APPLICATION (provided by applicant): The fundamental barrier to widespread treatment of latent TB infection as a public health intervention is the inability to predict the subsequent course of any given individual, the absence of a validated animal model to test new drug and vaccine therapies and the limited knowledge of host and bacterial factors required for entry into and exit from latency. The proposed studies will discover biomarkers to stratify risk of individuals with latent TB infection and promote their use in targeting preventive therapy, allowing individualized short course treatment regimens, and as surrogate endpoints in clinical trials. Clinical studies and the rabbit model will establish comparability in rates of replication and mutation rates, PET-CT findings and sites of reactivation, validating the use of the model to study new drugs, regimens and immunotherapies which can be rapidly translated into clinical trials. Understanding of the role of bacterial factor including low MICs in persistence, and the genetic mechanisms for loss of persistence phenotypes can provide a new focus for development of drugs, regimens and schedules uniquely active against persisting organisms. The program is composed of four research projects and two cores (administrative and clinical). Project 1, Biomarkers to Stratify risk of progression from latent TB infection to disease. Project 2, Validation and Application of a Model of Human TB-like Latency in Rabbits. Project 3, Biomarkers of Persistent TB Infection and TB Treatment relapse. Project 4, Bacterial Mechanisms and Host Pharmacokinetic. Factors that Determine Persistence in Paucibacillary TB. The clinical sites are in Seoul South Korea and Vitoria Brazil. The Principal Investigators are Dr. Jerrold J. Ellner, Boston Medical Center, Dr. Padmini Salgame, UMDNJ and David Alland, UMDNJ. The scientific teams are: Epidemiology and Clinical Studies, Drs. Robert Horburgh, Ray Cho, Reynaldo Dietze, Eddie Jone-Lopez, Karen Jacobson;Immunology and Biomarkers, Drs. Padmini Salgame, Rodrigo Rodrigues, Gilla Kaplan, Jerrold Ellner;Microbiology, Molecular Genetics and Antimicrobial Resistance, David Alland, Veronique Dartois, Bill Jacobs, JJ Collins;Animal Models, Drs. Padmini Salgame and Gilla Kaplan.
TB remains a global public health emergency compounded by increasing drug resistance. Better tools are needed to control TB worldwide. Perhaps most useful would be understanding of latent TB infection and persistence infection after treatment. The discovery of new markers for high and low risk individuals in terms of development of TB and adequacy of treatment would allow evidence-based determination of who to treat, how to treat and how long to treat both for prevention and cure.
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