Project 1 will apply systems approaches to identify Host Regulatory Gene (HRG) networks that determine the balance between asymptomatic MTB infection and TB disease progression. Our strategy is centered on our recent identification of transcriptomic signatures that predict progression to active tuberculosis (TB) in humans. By integrating our human transcriptomic signatures for MTB disease progression with network models of macrophage innate immunity, we have identified nearly 200 candidate HRGs of MTB infection. Leveraging our access to a vast and expanding repository of mice harboring ENU-induced incidental mutations, we will screen the HRG mouse mutants for altered MTB-induced innate and adaptive immunity in vivo. HRG mutants that alter TB disease progression will be advanced for detailed mechanistic analysis. MTB-regulated innate immunity networks, and networks governing the interface between innate and adaptive immunity will be exhaustively characterized in vitro and in vivo through systems-level profiling. We will collect host and MTB transcriptomes, targeted protein level changes, condition-specific ChlP-seq, and proteomic enhanceosome profiles of key host regulators from within matched samples of infected macrophages. These data will fuel modeling of both the bacterial and host response networks, predictions from which will drive a new round of candidate HRG evaluation, omics-scale data collection and additional modeling. Our ultimate modeling Aim: a novel integrated host/MTB network model will be tested using samples from humans, with both candidate mutant bacteria and specific host genes modulated by RNAi. In recent years, we have contributed substantially to the infrastructure needed for systems biology, including the development of key tools for data generation, analysis and modeling. We have generated an extensive compendium of innate regulatory networks that will serve as a foundation for the MTB studies proposed here. This project combines separate advances in immunology, transcriptomics, molecular genetics, ChlPseq, proteomics and network modeling to produce an experimentally grounded and verifiable systems-level

Public Health Relevance

Mycobacterium tuberculosis causes ~9 million new cases of active disease and 1.4 million deaths each year, and our tools to combat tuberculosis (TB) disease are universally outdated and overmatched. This project combines separate advances in systems biology and network modeling to produce an experimentally grounded and verifiable systems-level model of the host regulatory networks that affect TB progression.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
1U19AI106761-01
Application #
8577272
Study Section
Special Emphasis Panel (ZAI1-EC-M (M1))
Project Start
2013-06-21
Project End
2018-05-31
Budget Start
2013-06-21
Budget End
2014-05-31
Support Year
1
Fiscal Year
2013
Total Cost
$787,288
Indirect Cost
$299,244
Name
Seattle Biomedical Research Institute
Department
Type
DUNS #
070967955
City
Seattle
State
WA
Country
United States
Zip Code
98109
Zak, Daniel E; Tam, Vincent C; Aderem, Alan (2014) Systems-level analysis of innate immunity. Annu Rev Immunol 32:547-77
Urdahl, Kevin B (2014) Understanding and overcoming the barriers to T cell-mediated immunity against tuberculosis. Semin Immunol 26:578-87