Global Adaptation to a Lipid Environment Triggers the Dormancy-Related Phenotype of Mycobacterium tuberculosis

Abstract

Strong evidence supports the idea that fatty acids rather than carbohydrates are the main energy source of Mycobacterium tuberculosis during infection and latency. Despite that important role, a complete scenario of the bacterium’s metabolism when lipids are the main energy source is still lacking. Here we report the development of an in vitro model to analyze adaptation of M. tuberculosis during assimilation of long-chain fatty acids as sole carbon sources. The global lipid transcriptome revealed a shift toward the glyoxylate cycle, the overexpression of main regulators whiB3, dosR, and Rv0081, and the increased expression of several genes related to reductive stress. Our evidence showed that lipid storage seems to be the selected mechanism used by M. tuberculosis to ameliorate the assumed damage of reductive stress and that concomitantly the bacilli acquired a slowed-growth and drug-tolerant phenotype, all characteristics previously associated with the dormant stage. Additionally, intergenic regions were also detected, including the unexpected upregulation of tRNAs that suggest a new role for these molecules in the acquisition of a drug-tolerant phenotype by dormant bacilli. Finally, a set of lipid signature genes for the adaptation process was also identified. This in vitro model represents a suitable condition to illustrate the participation of reductive stress in drugs’ activity against dormant bacilli, an aspect scarcely investigated to date. This approach provides a new perspective to the understanding of latent infection and suggests the participation of previously undetected molecules.

CD36-Mediated Uptake of Surfactant Lipids by Human Macrophages Promotes Intracellular Growth of Mycobacterium tuberculosis

“…During in vitro infection, M.tb up-regulates genes involved in lipid metabolism (6, 49) and utilizes host lipids as a carbon source (46–48, 50). However, the source of the host lipids used by the bacteria remains less clear.…”

“…M.tb uses host lipids as a carbon source (46–48), which may contribute to the bacterium’s successful persister strategy (49, 50). TB results in disrupted host lipid metabolism during later stages of disease (51) and post-primary reactivation TB has historically been described as lipid pneumonia (52).…”

Acetate Dissimilation and Assimilation in Mycobacterium tuberculosis Depend on Carbon Availability

“…In vitro, nonreplicating M. tuberculosis uses externally provided fatty acids to generate lipid bodies (49). Inside lipidloaded macrophages, the pathogen acquires fatty acids from hydrolyzed cellular lipids and forms lipid inclusions, which act as an internal carbon storage (50).…”

Mycobacterium marinum Degrades Both Triacylglycerols and Phospholipids from Its Dictyostelium Host to Synthesise Its Own Triacylglycerols and Generate Lipid Inclusions

“…Intracellular mycobacteria have been seen in the vicinity of LDs [3, 6] and are able to access these lipid stores to acquire fatty acids (FAs; [7]) to build up their own intracytosolic lipid inclusions (ILIs) for times of nutrient deprivation [6]. Interestingly, the formation of ILIs is a main characteristic of dormant bacteria [7, 8] and with the help of an in vitro dormancy model it was proposed that FAs, released form bacterial TAGs, serve as carbon source to initiate replicative activities [9]. …”