Transcription profiling of genes encoding components of the respiratory chain and the
ATP synthesizing apparatus of Mycobacterium tuberculosis was conducted in vivo in the infected mouse lung, and in vitro in bacterial cultures subjected to gradual
oxygen depletion and to
nitric oxide treatment. Transcript levels changed dramatically as
infection progressed from bacterial exponential multiplication (acute
infection) to cessation of bacterial growth (
chronic infection) in response to host immunity. The
proton-pumping type-I
NADH dehydrogenase and the aa3-type
cytochrome c oxidase were strongly down-regulated. Concurrently, the less energy-efficient
cytochrome bd
oxidase was transiently up-regulated. The
nitrate transporter NarK2 was also up-regulated, indicative of increased
nitrate respiration. The reduced efficiency of the respiratory chain was accompanied by decreased expression of
ATP synthesis genes. Thus, adaptation of M.
tuberculosis to host immunity involves three successive respiratory states leading to decreased energy production. Decreased bacterial counts in mice infected with a cydC mutant (defective in the
cytochrome bd
oxidase-associated transporter) at the transition to
chronic infection provided initial evidence that the bd
oxidase pathway is required for M.
tuberculosis adaptation to host immunity. In vitro, NO treatment and
hypoxia caused a switch from transcription of type I to type II
NADH dehydrogenase. Moreover,
cytochrome bd
oxidase expression increased, but
cytochrome c oxidase expression decreased slightly (
nitric oxide) or not at all (
hypoxia). These specific differences in respiratory metabolism during M.
tuberculosis growth arrest in vitro and in vivo will guide manipulation of in vitro conditions to model bacterial adaptation to host immunity.