Although only a minority of individuals infected with Mycobacterium tuberculosis progress to active disease, host factors associated with progression are only poorly understood. Recent data show that metabolic risk factors such as low body-mass index, metabolic syndrome and type 2 diabetes mellitus are strong predictors of an individual's risk of progressing to active disease after infection. Further, growing evidence suggests a link between an individual's metabolic state and control of human macrophage and dendritic cell activation and differentiation pathways. Here, we propose to identify key host metabolic pathways involved in TB progression in a genetic study of an existing TB exposed cohort and then test these associations by performing observational studies in humans and intervention studies in guinea pig models. First, we will leverage our existing cohort of microbiologically confirmed TB index cases and their exposed, infected household contacts who have remained disease free for two years after exposure. Using a nested case control study design, we will assess the impact of genetic variants known to affect key metabolic traits as well as rare coding variants on TB progression using exome chips that are optimized for the Peruvian population in which we work. Second, we will use the results of this study to guide further validation of these determinants through transcriptional profiling of human myeloid cells from cases and exposed non-diseased controls. In a sub-study, we will also these exome chip and transcriptional profiling data to identify the genes involved in dendritic cell maturation as assessed by genes related to CD1, interleukin-1 and NFkappaB. To further explore the impact of these metabolic and immune pathways, we will conduct TB infection experiments in guinea pigs in which metabolic status is modified through dietary and pharmacological interventions with the aim of identifying possible therapeutic interventions that could moved to human trials in future work.

Public Health Relevance

Although human metabolic risk factors are emerging as strong predictors of TB suscepfibility, the mechanisms through they affect the risk and severity of disease have not been eludicated. A better understanding ofthe molecular pathways that link metabolic and immune responses might provide targets forthe development of therapeutic intervenfions. Here, we use human genefic and transcripfional studies and a guinea pig model to explore these pathways.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Brigham and Women's Hospital
United States
Zip Code
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
Madigan, Cressida A; Cambier, C J; Kelly-Scumpia, Kindra M et al. (2017) A Macrophage Response to Mycobacterium leprae Phenolic Glycolipid Initiates Nerve Damage in Leprosy. Cell 170:973-985.e10
Moody, D Branch (2017) How T cells grasp mycobacterial lipid antigens. Proc Natl Acad Sci U S A 114:13312-13314
Brennan, Patrick J; Cheng, Tan-Yun; Pellicci, Daniel G et al. (2017) Structural determination of lipid antigens captured at the CD1d-T-cell receptor interface. Proc Natl Acad Sci U S A 114:8348-8353
Rao, Deepak A; Gurish, Michael F; Marshall, Jennifer L et al. (2017) Pathologically expanded peripheral T helper cell subset drives B cells in rheumatoid arthritis. Nature 542:110-114

Showing the most recent 10 out of 49 publications