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In vivo gene silencing identifies the Mycobacterium tuberculosis proteasome as essential for the bacteria to persist in mice.

TitleIn vivo gene silencing identifies the Mycobacterium tuberculosis proteasome as essential for the bacteria to persist in mice.
Publication TypeJournal Article
Year of Publication2007
AuthorsGandotra S, Schnappinger D, Monteleone M, Hillen W, Ehrt S
JournalNat Med
Volume13
Issue12
Pagination1515-20
Date Published2007 Dec
ISSN1546-170X
KeywordsAnimals, Bacterial Proteins, Disease Models, Animal, Female, Gene Silencing, Green Fluorescent Proteins, Interferon-gamma, Lung, Mice, Mice, Inbred C57BL, Microscopy, Fluorescence, Models, Biological, Mutation, Mycobacterium tuberculosis, Proteasome Endopeptidase Complex
Abstract

The success of Mycobacterium tuberculosis (Mtb) as a human pathogen relies on its ability to resist eradication by the immune system. The identification of mechanisms that enable Mtb to persist is key for finding ways to limit latent tuberculosis, which affects one-third of the world's population. Here we show that conditional gene silencing can be used to determine whether an Mtb gene required for optimal growth in vitro is also important for virulence and, if so, during which phase of an infection it is required. Application of this approach to the prcBA genes, which encode the core of the mycobacterial proteasome, revealed an unpredicted requirement of the core proteasome for the persistence of Mtb during the chronic phase of infection in mice. Proteasome depletion also attenuated Mtb in interferon-gamma-deficient mice, pointing to a function of the proteasome beyond defense against the adaptive immune response. Genes that are essential for growth in vitro, in vivo or both account for approximately 20% of Mtb's genome. Conditional gene silencing could therefore facilitate the validation of up to 800 potential Mtb drug targets and improve our understanding of host-pathogen dynamics.

DOI10.1038/nm1683
Alternate JournalNat Med
PubMed ID18059281
PubMed Central IDPMC3174471
Grant ListR01 AI063446 / AI / NIAID NIH HHS / United States
R01 AI063446-02 / AI / NIAID NIH HHS / United States
AI63446 / AI / NIAID NIH HHS / United States

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