Genome-Wide Requirements for Mycobacterium tuberculosis Adaptation and Survival in Macrophages

Macrophages are central to host defense against microbes, but intracellular pathogens have evolved to evade their antimicrobial functions. Mycobacterium tuberculosis (MTB) has successfully exploited macrophages as its primary niche in vivo, but the bacterial genome-wide requirements that promote its...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 102; no. 23; pp. 8327 - 8332
Main Authors Rengarajan, Jyothi, Bloom, Barry R., Rubin, Eric J.
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 07.06.2005
National Acad Sciences
SeriesFrom the Cover
Subjects
Adaptation, Physiological - genetics
Animals
Bacteria
Biological Sciences
Biological Transport - genetics
Gene Expression Profiling
Gene Expression Regulation, Bacterial
Genes
Genes, Bacterial - genetics
Genetic screening
Genome, Bacterial
Genomics
Infections
Macrophages
Macrophages - microbiology
Mice
Mice, Inbred C57BL
Microbiology
Mutation
Mycobacterium tuberculosis
Mycobacterium tuberculosis - genetics
Mycobacterium tuberculosis - growth & development
Operon - genetics
Operons
Organ Specificity
Phosphates
Phosphates - metabolism
Transposons
Tuberculosis
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Summary:Macrophages are central to host defense against microbes, but intracellular pathogens have evolved to evade their antimicrobial functions. Mycobacterium tuberculosis (MTB) has successfully exploited macrophages as its primary niche in vivo, but the bacterial genome-wide requirements that promote its intracellular survival remain undefined. Here we comprehensively identify the MTB genes required for survival by screening for transposon mutants that fail to grow within primary macrophages. We identify mutants showing decreased growth in macrophage environments that model stages of the host immune response. By systematically analyzing several biologically relevant data sets, we have been able to identify putative pathways that could not be predicted by genome organization alone. In one example, phosphate transport, requiring physically unlinked genes, was found to be critical for MTB growth in macrophages and important for establishing persistent infection in lungs. Remarkably, the majority of MTB genes found by this analysis to be required for survival are constitutively expressed rather than regulated by macrophages, revealing the host-adapted lifestyle of an evolutionarily selected intracellular pathogen.
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Abbreviations: TraSH, transposon site hybridization; MTB, Mycobacterium tuberculosis; moi, multiplicity of infection.
To whom correspondence should be addressed. E-mail: erubin@hsph.harvard.edu.
Author contributions: J.R. and E.J.R. designed research; J.R. performed research; J.R., B.R.B., and E.J.R. contributed new reagents/analytic tools; J.R. analyzed data; and J.R., B.R.B., and E.J.R. wrote the paper.
Contributed by Barry R. Bloom, April 20, 2005
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0503272102