Date

June 2012

Document Type

Thesis

Degree Name

M.S.

Department

Dept. of Medical Informatics and Clinical Epidemiology

Institution

Oregon Health & Science University

Abstract

Tuberculosis remains a major burden on global health, infecting an estimated one--third of the world’s population. A major obstacle to detecting and overcoming tuberculosis is understanding how Mycobacterium tuberculosis persists and multiplies inside host macrophages and dendritic cells, and the unique roles of the two immune cells in eliminating the pathogen. Here, we constructed a Physical Module Network (PMN) using gene expression data from in vitro experiments that simulate the reactive oxygen and nitrogen species and hypoxia encountered by M. tuberculosis within host phagocytes. We also used the same expression data to discover modules using Weighted Gene Correlation Network Analysis (WGCNA). Fifteen viable PMN modules were discovered, one of which contains a substantial portion of the DosR regulon and is enriched for GO terms related to nitrosative stress and hypoxia. Of the seventeen significant WGCNA modules, five significantly overlapped with PMN modules, including the DosR--associated module. Following module discovery, in a second dataset we tested the PMN modules for differential expression of M. tuberculosis infecting human macrophages and dendritic cells. At one hour post--infection the modules are not differentially expressed between M. tuberculosis infecting macrophages and dendritic cells. After 18 hours of infection all modules are differentially expressed, indicating difference in the sustained strategies employed by M. tuberculosis infecting macrophages and dendritic cells.

Identifier

doi:10.6083/M4Z60M1G

School

School of Medicine

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