igr Genes and Mycobacterium tuberculosis cholesterol metabolism.
Recently, cholesterol was identified as a physiologically important nutrient for Mycobacterium tuberculosis survival in chronically infected mice. However, it remained unclear precisely when cholesterol is available to the bacterium and what additional bacterial functions are required for its metabolism. Here, we show that the igr locus, which we previously found to be essential for intracellular growth and virulence of M. tuberculosis, is required for cholesterol metabolism. While igr-deficient strains grow identically to the wild type in the presence of short- and long-chain fatty acids, the growth of these bacteria is completely inhibited in the presence of cholesterol. Interestingly, this mutant is still able to respire under cholesterol-dependent growth inhibition, suggesting that the bacteria can metabolize other carbon sources during cholesterol toxicity. Consistent with this hypothesis, we found that the growth-inhibitory effect of cholesterol in vitro depends on cholesterol import, as mutation of the mce4 sterol uptake system partially suppresses this effect. In addition, the Delta igr mutant growth defect during the early phase of disease is completely suppressed by mutating mce4, implicating cholesterol intoxication as the primary mechanism of attenuation. We conclude that M. tuberculosis metabolizes cholesterol throughout infection.
Chang
Jennifer C
JC
Seattle Biomedical Research Institute, 307 Westlake Ave N, Ste 500. Seattle, WA 98109, USA.
Miner
Maurine D
MD
Pandey
Amit K
AK
Gill
Wendy P
WP
Harik
Nada S
NS
Sassetti
Christopher M
CM
Sherman
David R
DR
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000502:physiology*; D002784:Cholesterol / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000235:genetics* / Q000254:growth & development* / Q000378:metabolism
D001426:Bacterial Proteins; C510664:Mce4A protein, Mycobacterium tuberculosis; D000255:Adenosine Triphosphate; D002784:Cholesterol