Genome-Wide RNAi Screen in \(IFN-\gamma-Treated\) Human Macrophages Identifies Genes Mediating Resistance to the Intracellular Pathogen Francisella tularensis
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CitationZhou, Hongwei, Glen M. DeLoid, Erica Browning, David James Gregory, Fengxiao Tan, Alice Bedugnis, Amy Imrich, et al. 2012. Genome-wide RNAi screen in \(IFN-\gamma-treated\) human macrophages identifies genes mediating resistance to the intracellular pathogen Francisella tularensis. PLoS ONE 7(2): e31752.
AbstractInterferon-gamma \((IFN-\gamma)\) inhibits intracellular replication of Francisella tularensis in human monocyte-derived macrophages (HMDM) and in mice, but the mechanisms of this protective effect are poorly characterized. We used genome-wide RNA interference (RNAi) screening in the human macrophage cell line THP-1 to identify genes that mediate the beneficial effects of \(IFN-\gamma\) on F. tularensis infection. A primary screen identified ~200 replicated candidate genes. These were prioritized according to mRNA expression in \(IFN-\gamma-primed\) and F. tularensis-challenged macrophages. A panel of 20 top hits was further assessed by re-testing using individual shRNAs or siRNAs in THP-1 cells, HMDMs and primary human lung macrophages. Six of eight validated genes tested were also found to confer resistance to Listeria monocytogenes infection, suggesting a broadly shared host gene program for intracellular pathogens. The F. tularensis-validated hits included ‘druggable’ targets such as TNFRSF9, which encodes CD137. Treating HMDM with a blocking antibody to CD137 confirmed a beneficial role of CD137 in macrophage clearance of F. tularensis. These studies reveal a number of important mediators of \(IFN-\gamma\) activated host defense against intracellular pathogens, and implicate CD137 as a potential therapeutic target and regulator of macrophage interactions with Francisella tularensis.
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