The Animal Models Core (D) is located within the Mycobacteriology Laboratory on the campus of Colorado State University. The Animal Infection Core is multidisciplinary with the expertise, personnel and facilities to model Mtb infection in guinea pigs with drug susceptible and resistant human clinical isolates as well as laboratory Mtb strains with targeted gene mutations. Our laboratory is also experienced and well equipped to model Mtb infection in guinea pigs with concurrent non-communicable diseases that are known TB risk factors in humans. Relevant to this proposal, we have developed the first ever model of Mtb infection in guinea pigs with diet-induced insulin resistance and type 2 diabetes that accurately mimics the comorbidity of tuberculosis and emerging noncommunicable diseases. In addition, we have designed and validated novel strategies to quantify pulmonary and extra-pulmonary tuberculosis disease burden in guinea pigs in response to experimental aerosol infection with drug susceptible and multi-drug resistant strains of Mycobacterium tuberculosis. We have recently characterized the profound alterations in systemic and cellular metabolism in response to Mycobacterium tuberculosis infection alone and demonstrated how preexisting alterations in host metabolism influences host susceptibility and in vivo disease progression. The Animal Models Core will parallel human cohort studies to 1) identify host metabolic determinants of tuberculosis disease control and progression and 2) use metabolomics to discover bacterial determinates of drug resistance and the discovery of host- and pathogen-derived biomarkers for tuberculosis diagnosis. Using the guinea pig model to study altered host metabolism associated with Mycobacterium tuberculosis infection has not only improved our understanding of the host-pathogen interaction but has identified potentially important therapeutic strategies that can be used as adjunct therapy in combination with conventional antimicrobial drug therapy. To fully exploit this model, the substantial existing core capabilities will be expanded to discover and validate additional biomarkers of altered host metabolism in guinea pigs infected with drug susceptible and drug resistant Mycobacterium tuberculosis.

Public Health Relevance

Many ofthe over 1.4 million human deaths caused by Mycobacterium tuberculosis occur in individuals with preexisisting medical conditions or risk factors. The Animal Models Core (D) models tuberculosis in guinea pigs to mimic how clinical disease is controlled or progresses to death in humans. Parallel studies in guinea pigs and humans will enable us to understand how the bacterium sun/ives in vivo in human patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI111224-06
Application #
9857539
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2020-02-01
Budget End
2021-01-31
Support Year
6
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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
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
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