Systematic, multiparametric analysis of Mycobacterium tuberculosis intracellular infection offers insight into coordinated virulence

• DOI: 10.1371/journal.ppat.1006363
• Publication Date: 2017-05-15T18:11:38Z
• Authors: Amy K. Barczak; Roi Avraham; Shantanu Singh; Samantha S. Luo; Wei Ran Zhang; Mark-Anthony Bray; Amelia E. Hinman; Matthew Thompson; Raymond M. Nietupski; Aaron Golas; Paul Montgomery; Michael Fitzgerald; Roger S. Smith; Dylan W. White; Anna D. Tischler; Anne E. Carpenter; Deborah T. Hung
• Keywords: Intracellular parasite; Phenotypic screening; Virulence factor

A key to the pathogenic success of Mycobacterium tuberculosis (Mtb), causative agent tuberculosis, is capacity survive within host macrophages. Although several factors required for this survival have been identified, a comprehensive knowledge such and how they work together manipulate environment benefit bacterial are not well understood. To systematically identify Mtb intracellular growth, we screened an arrayed, non-redundant transposon mutant library by high-content imaging characterize mutant-macrophage interaction. Based on combination features, identified mutants impaired survival. We then characterized phenotype infection with each profiling induced macrophage cytokine response. Taking systems-level approach understanding biology mutants, performed multiparametric analysis combining pathogen phenotypes predict functional relationships between based clustering. Strikingly, defective in two well-known virulence factors, ESX-1 protein secretion system lipid phthiocerol dimycocerosate (PDIM), clustered together. Building upon shared loss type I interferon (IFN) response infection, found that PDIM production export coordinated ESX-1-substrates, phagosomal permeabilization, downstream induction IFN Multiparametric clustering also novel genes Thus, can be used play role infection.