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Genome-wide screen for Mycobacterium tuberculosis genes that regulate host immunity.

TitleGenome-wide screen for Mycobacterium tuberculosis genes that regulate host immunity.
Publication TypeJournal Article
Year of Publication2010
AuthorsBeaulieu AM, Rath P, Imhof M, Siddall ME, Roberts J, Schnappinger D, Nathan CF
JournalPLoS One
Volume5
Issue12
Paginatione15120
Date Published2010 Dec 10
ISSN1932-6203
KeywordsAnimals, DNA Transposable Elements, Female, Gene Expression Regulation, Bacterial, Genes, Bacterial, Genome, Bacterial, Interleukin-12 Subunit p40, Interleukin-6, Macrophages, Mice, Mice, Inbred C57BL, Microscopy, Fluorescence, Mutation, Mycobacterium tuberculosis, Tumor Necrosis Factor-alpha
Abstract

In spite of its highly immunogenic properties, Mycobacterium tuberculosis (Mtb) establishes persistent infection in otherwise healthy individuals, making it one of the most widespread and deadly human pathogens. Mtb's prolonged survival may reflect production of microbial factors that prevent even more vigorous immunity (quantitative effect) or that divert the immune response to a non-sterilizing mode (qualitative effect). Disruption of Mtb genes has produced a list of several dozen candidate immunomodulatory factors. Here we used robotic fluorescence microscopy to screen 10,100 loss-of-function transposon mutants of Mtb for their impact on the expression of promoter-reporter constructs for 12 host immune response genes in a mouse macrophage cell line. The screen identified 364 candidate immunoregulatory genes. To illustrate the utility of the candidate list, we confirmed the impact of 35 Mtb mutant strains on expression of endogenous immune response genes in primary macrophages. Detailed analysis focused on a strain of Mtb in which a transposon disrupts Rv0431, a gene encoding a conserved protein of unknown function. This mutant elicited much more macrophage TNF╬▒, IL-12p40 and IL-6 in vitro than wild type Mtb, and was attenuated in the mouse. The mutant list provides a platform for exploring the immunobiology of tuberculosis, for example, by combining immunoregulatory mutations in a candidate vaccine strain.

DOI10.1371/journal.pone.0015120
Alternate JournalPLoS One
PubMed ID21170273
PubMed Central IDPMC3000826
Grant ListT32 AI007621 / AI / NIAID NIH HHS / United States
T32 AI07621 / AI / NIAID NIH HHS / United States

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