Systems Genetics of Tuberculosis: Program Abstract: Mycobacterium tuberculosis (Mtb) infection outcomes are highly variable, creating a great challenge in TB control; how do we identify those that are genuinely at risk and deliver an intervention that will be effective for that individual? The biological determinants of Mtb infection outcome have been difficult to define largely because multiple variables are involved, which include genetic variation in host and pathogen and non-genetic environmental factors. To overcome this complexity, we leveraged new mammalian and bacterial genetic resources to create a model system that can be used to study the effect of each of these variables in isolation and in combination. Host diversity is incorporated using mice from the ?Collaborative Cross? (CC), a newly generated reference panel of inbred mice that reflects the diversity of an outbred population. Bacterial variation is incorporated using large panels of Mtb strains that reflect both naturally- and experimentally-generated diversity. Using this highly-tractable system, the effect of controlled interventions can be assessed, and high-resolution phenotyping can be applied to differentiate different TB-related disease states. Three inter-related scientific projects will use this uniquely tractable experimental system to: 1) Define host determinants of TB susceptibility, 2) Identify bacterial determinants of host-pathogen preference. 3) Investigate the basis for TB vaccine efficacy in genetically-diverse populations Through collaboration with two essential Scientific Cores focused on Mouse and Human genetics and one Administrative Core, we will accomplish our ultimate scientific goals: to characterize the mechanisms underlying tuberculosis pathogenesis, extend these observations to human clinical cohorts, and use these insights to rationally-design more effective vaccines. !

Public Health Relevance

Systems Genetics of Tuberculosis: Project Narrative. Understanding the biological factors that control an individual's susceptibility to tuberculosis would enable the rational design of more effective interventions. This project will take advantage of new strategies in mouse and bacterial genetics to identify the critical factors that determine the outcome of this infection, and leverage human cohorts to understand how these mechanisms affect tuberculosis in the natural setting.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI132130-04
Application #
9985712
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Lacourciere, Karen A
Project Start
2017-08-05
Project End
2022-07-31
Budget Start
2020-08-01
Budget End
2021-07-31
Support Year
4
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
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Olive, Andrew J; Smith, Clare M; Kiritsy, Michael C et al. (2018) The Phagocyte Oxidase Controls Tolerance to Mycobacterium tuberculosis Infection. J Immunol 201:1705-1716