The absence of an effective vaccine for tuberculosis means that TB control relies on the early diagnosis and effective treatment of infectious cases, which is compromised by the relatively low sensitivity and specificity of standard diagnostic tools. Because TB infection most often results in a chronic asymptomatic state, prevention of disease by targeting those who are infected, but not yet ill, has been difficult to implement in high burden settings where more than half of the population is TB infected. The long duration of treatment necessary to achieve high cure rates and the emergence and spread of drug resistant organisms have further undermined the potential impact of national TB control programs. Our proposed plan responds to these research priorities and grows out of a series of recent research findings from our own groups and others that suggest an innovative interdisciplinary approach to the discovery of basic mechanisms through. Our proposed project begins with the identification and longitudinal follow-up of patients diagnosed with active TB and their household contacts. Patients that progress to active TB disease (progressors) are followed for disease outcomes, including relapse, and household contacts are followed for evidence of TB infection and disease. This design and our extensive longitudinal follow up capabilities will allow us to identify and characterize TB index cases and their exposed household contacts through careful clinical and epidemiologic studies, human genomics (by exome sequencing) human genetics (by exome chip), transcriptomics, and metabolomics. We have established Cores in Human subjects, Bio-informatics, and Metabolomics that will work in parallel to identify targets including pathways linking human metabolism and immune response, T cells involved in Mtb response, pathogen determinants of drug resistance and pathogen-shed markers of clinical TB phenotypes. Each project includes validation of these targets in the guinea pig model. Based on our results, we will then go on to test specific interventions in the animal model, focusing in particular on pharmacologic agents that alter human metabolic and immune responses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI111224-07
Application #
10089381
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Lacourciere, Karen A
Project Start
2015-02-01
Project End
2022-01-31
Budget Start
2021-02-01
Budget End
2022-01-31
Support Year
7
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
James, Charlotte A; Yu, Krystle K Q; Gilleron, Martine et al. (2018) CD1b Tetramers Identify T Cells that Recognize Natural and Synthetic Diacylated Sulfoglycolipids from Mycobacterium tuberculosis. Cell Chem Biol 25:392-402.e14
Mizoguchi, Fumitaka; Slowikowski, Kamil; Wei, Kevin et al. (2018) Functionally distinct disease-associated fibroblast subsets in rheumatoid arthritis. Nat Commun 9:789
Davenport, Emma E; Amariuta, Tiffany; Gutierrez-Arcelus, Maria et al. (2018) Discovering in vivo cytokine-eQTL interactions from a lupus clinical trial. Genome Biol 19:168
Carette, Xavier; Platig, John; Young, David C et al. (2018) Multisystem Analysis of Mycobacterium tuberculosis Reveals Kinase-Dependent Remodeling of the Pathogen-Environment Interface. MBio 9:
Lehmann, Johannes; Cheng, Tan-Yun; Aggarwal, Anup et al. (2018) An Antibacterial ?-Lactone Kills Mycobacterium tuberculosis by Disrupting Mycolic Acid Biosynthesis. Angew Chem Int Ed Engl 57:348-353
Wun, Kwok S; Reijneveld, Josephine F; Cheng, Tan-Yun et al. (2018) T cell autoreactivity directed toward CD1c itself rather than toward carried self lipids. Nat Immunol 19:397-406
Moody, D Branch; Cotton, Rachel N (2017) Four pathways of CD1 antigen presentation to T cells. Curr Opin Immunol 46:127-133
Critchley, Julia A; Restrepo, Blanca I; Ronacher, Katharina et al. (2017) Defining a Research Agenda to Address theĀ Converging Epidemics of Tuberculosis and Diabetes: Part 1: Epidemiology and Clinical Management. Chest 152:165-173
Ronacher, Katharina; van Crevel, Reinout; Critchley, Julia A et al. (2017) Defining a Research Agenda to Address theĀ Converging Epidemics of Tuberculosis and Diabetes: Part 2: Underlying Biologic Mechanisms. Chest 152:174-180
Hinks, A; Bowes, J; Cobb, J et al. (2017) Fine-mapping the MHC locus in juvenile idiopathic arthritis (JIA) reveals genetic heterogeneity corresponding to distinct adult inflammatory arthritic diseases. Ann Rheum Dis 76:765-772

Showing the most recent 10 out of 49 publications