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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI111276-07
Application #
9755331
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Mendez, Susana
Project Start
2014-08-01
Project End
2021-07-31
Budget Start
2019-08-01
Budget End
2020-07-31
Support Year
7
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Rutgers University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078795851
City
Newark
State
NJ
Country
United States
Zip Code
07103
Vilchèze, Catherine; Copeland, Jacqueline; Keiser, Tracy L et al. (2018) Rational Design of Biosafety Level 2-Approved, Multidrug-Resistant Strains of Mycobacterium tuberculosis through Nutrient Auxotrophy. MBio 9:
Peloquin, Charles A; Phillips, Patrick P J; Mitnick, Carole D et al. (2018) Increased Doses Lead to Higher Drug Exposures of Levofloxacin for Treatment of Tuberculosis. Antimicrob Agents Chemother 62:
Singhania, Akul; Verma, Raman; Graham, Christine M et al. (2018) A modular transcriptional signature identifies phenotypic heterogeneity of human tuberculosis infection. Nat Commun 9:2308
Geadas, Carolina; Acuna-Villaorduna, Carlos; Mercier, Gustavo et al. (2018) FDG-PET/CT activity leads to the diagnosis of unsuspected TB: a retrospective study. BMC Res Notes 11:464
Esmail, Hanif; Lai, Rachel P; Lesosky, Maia et al. (2018) Complement pathway gene activation and rising circulating immune complexes characterize early disease in HIV-associated tuberculosis. Proc Natl Acad Sci U S A 115:E964-E973
Vilchèze, Catherine; Kim, John; Jacobs Jr, William R (2018) Vitamin C Potentiates the Killing of Mycobacterium tuberculosis by the First-Line Tuberculosis Drugs Isoniazid and Rifampin in Mice. Antimicrob Agents Chemother 62:
Acuña-Villaorduña, Carlos; Jones-López, Edward C; Fregona, Geisa et al. (2018) Intensity of exposure to pulmonary tuberculosis determines risk of tuberculosis infection and disease. Eur Respir J 51:
Colangeli, Roberto; Jedrey, Hannah; Kim, Soyeon et al. (2018) Bacterial Factors That Predict Relapse after Tuberculosis Therapy. N Engl J Med 379:823-833
Ma, Y; Horsburgh, C R; White, L F et al. (2018) Quantifying TB transmission: a systematic review of reproduction number and serial interval estimates for tuberculosis. Epidemiol Infect 146:1478-1494
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

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