Abstract
Mycobacterium tuberculosis (Mtb) is an obligate human pathogen that can adapt to the various nutrients available during its life cycle. However, in the nutritionally stringent environment of the macrophage phagolysosome, Mtb relies mainly on cholesterol. In previous studies, we demonstrated that Mtb can accumulate and utilize cholesterol as the sole carbon source. However, a growing body of evidence suggests that a lipid-rich environment may have a much broader impact on the pathogenesis of Mtb infection than previously thought. Therefore, we applied high-resolution transcriptome profiling and the construction of various mutants to explore in detail the global effect of cholesterol on the tubercle bacillus metabolism. The results allow re-establishing the complete list of genes potentially involved in cholesterol breakdown. Moreover, we identified the modulatory effect of vitamin B12 on Mtb transcriptome and the novel function of cobalamin in cholesterol metabolite dissipation which explains the probable role of B12 in Mtb virulence. Finally, we demonstrate that a key role of cholesterol in mycobacterial metabolism is not only providing carbon and energy but involves also a transcriptome remodeling program that helps in developing tolerance to the unfavorable host cell environment far before specific stress-inducing phagosomal signals occur.
Highlights
Mycobacterium tuberculosis (Mtb) is an obligate human pathogen that can adapt to the various nutrients available during its life cycle
Genes demonstrating a change in expression with a false discovery rate (FDR) of
The presence of the 9OHAD intermediate in lipid samples of the ΔfadD19ΔechA19ΔkstD triple mutant growing on cholesterol demonstrated that cholesterol sidechain metabolism in Mtb devoid of echA19 and fadD19 genes was unaffected (Fig. 3C). These results indicate that despite significant induction by cholesterol, both genes may not be directly involved in cholesterol breakdown or other Mtb proteins within a large group of acyl-CoA ligases and enoyl-CoA hydratases may complement their essential enzymatic functions. hsd4B is the only cholesterol-induced gene annotated as coding for the probable (R)-enoyl-CoA hydratase that catalyzes hydration in the 2 nd round of side-chain β-oxidation (Fig. 2B)
Summary
Mycobacterium tuberculosis (Mtb) is an obligate human pathogen that can adapt to the various nutrients available during its life cycle. A growing body of evidence suggests that a lipid-rich environment may have a much broader impact on the pathogenesis of Mtb infection than previously thought. Advantage over microarrays because it can produce perfectly quantified transcriptomes with a higher resolution, the growing body of evidence suggests that the lipid-rich environment may have a much broader impact on the Mtb transcriptome than previously thought. Cholesterol is the key constituent of the Mtb lipid environment during pathogenesis, a complete transcriptomic landscape of the tubercle bacillus utilizing cholesterol as a sole carbon source is still lacking. In this study, we applied RNA-Seq and constructed and analyzed specific mutants to precisely describe Mtb metabolic adaptations during growth on cholesterol as the only carbon and energy source and explain how cholesterol may facilitate the establishment of persistent infection
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
