Inhibition of respiration by nitric oxide induces a Mycobacterium tuberculosis dormancy program.

TitleInhibition of respiration by nitric oxide induces a Mycobacterium tuberculosis dormancy program.
Publication TypeJournal Article
Year of Publication2003
AuthorsVoskuil MI, Schnappinger D, Visconti KC, Harrell MI, Dolganov GM, Sherman DR, Schoolnik GK
JournalJ Exp Med
Volume198
Issue5
Pagination705-13
Date Published2003 Sep 01
ISSN0022-1007
KeywordsMycobacterium tuberculosis, Nitric Oxide, Nitric Oxide Donors, Nitric Oxide Synthase, Oxygen Consumption, Triazenes
Abstract

An estimated two billion persons are latently infected with Mycobacterium tuberculosis. The host factors that initiate and maintain this latent state and the mechanisms by which M. tuberculosis survives within latent lesions are compelling but unanswered questions. One such host factor may be nitric oxide (NO), a product of activated macrophages that exhibits antimycobacterial properties. Evidence for the possible significance of NO comes from murine models of tuberculosis showing progressive infection in animals unable to produce the inducible isoform of NO synthase and in animals treated with a NO synthase inhibitor. Here, we show that O2 and low, nontoxic concentrations of NO competitively modulate the expression of a 48-gene regulon, which is expressed in vivo and prepares bacilli for survival during long periods of in vitro dormancy. NO was found to reversibly inhibit aerobic respiration and growth. A heme-containing enzyme, possibly the terminal oxidase in the respiratory pathway, likely senses and integrates NO and O2 levels and signals the regulon. These data lead to a model postulating that, within granulomas, inhibition of respiration by NO production and O2 limitation constrains M. tuberculosis replication rates in persons with latent tuberculosis.

DOI10.1084/jem.20030205
Alternate JournalJ Exp Med
PubMed ID12953092
PubMed Central IDPMC2194188
Grant ListR01 AI044826 / AI / NIAID NIH HHS / United States
AI 44826 / AI / NIAID NIH HHS / United States

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