The Modeling Core will integrate data from Projects 1 and 2 and construct a joint host and pathogen gene regulatory network (GRN) model by regression-based inference of direct and indirect inter-organismal influences on gene expression. This cross-species GRN model will link quantitative phenotypes to causal environmental and genetic triggers that influence the outcome of TB infection, specifically susceptibility, resistance, infection progression, persistence, and clearance. Central to these predictive models are machine learning algorithms - cMonkey and Inferelator - that will work in tandem to discover groups of genes that are conditionally co-regulated by combinatorial environmental (e.g. pH) and genetic (e.g;transcription factors) influences. The data integration strategies incorporated into these algorithms will overcome several challenges: (1) technical and biological noise in systems biology data;(2) lack of functional information for over 50% of all genes in the genome;(3) lack of detailed knowledge of regulatory mechanisms;and (4) incomplete knowledge of the environmental space to which both the host and MTB networks have adapted. The Modeling Core will reverse engineer the architecture of GRNs directly from data while simultaneously learning the associated dynamics of transcriptional regulation. Moreover, genes of unknown function will be integrated into the network based on their co-expression patterns, and other shared features such as interactions, phylogeny, and cis-regulatory elements;making it possible to discover additional genes that might be critical for outcome of infection. Preliminary GRN models for both MTB and BMMO have already been constructed, and analysis of these models has demonstrated that they recapitulate existing knowledge and predict new genes that might, influence the outcome of MTB infection. These model predictions have provided guidance for experimental designs and priorities in both Projects.

Public Health Relevance

Mycobacterium tuberculosis (MTB) causes ~9 million new cases of active disease and 1.4 million deaths each year. By constructing predictive models that integrate systems-scale data of both MTB and host cells, the Modeling Core will provide a detailed mechanistic framework that will facilitate elucidation of mechanisms that enable MTB to infect and persist in the host, and that drive the host response to MTB infection

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1-EC-M)
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Seattle Biomedical Research Institute
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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