Metabolic Versatility of Mycobacterium tuberculosis during Infection and Dormancy

Abstract

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is a highly successful intracellular pathogen with the ability to withstand harsh conditions and reside long-term within its host. In the dormant and persistent states, the bacterium tunes its metabolism and is able to resist the actions of antibiotics. One of the main strategies Mtb adopts is through its metabolic versatility—it is able to cometabolize a variety of essential nutrients and direct these nutrients simultaneously to multiple metabolic pathways to facilitate the infection of the host. Mtb further undergo extensive remodeling of its metabolic pathways in response to stress and dormancy. In recent years, advancement in systems biology and its applications have contributed substantially to a more coherent view on the intricate metabolic networks of Mtb. With a more refined appreciation of the roles of metabolism in mycobacterial infection and drug resistance, and the success of drugs targeting metabolism, there is growing interest in further development of anti-TB therapies that target metabolism, including lipid metabolism and oxidative phosphorylation. Here, we will review current knowledge revolving around the versatility of Mtb in remodeling its metabolism during infection and dormancy, with a focus on central carbon metabolism and lipid metabolism.

Host- and age-dependent transcriptional changes in Mycobacterium tuberculosis cell envelope biosynthesis genes after exposure to human alveolar lining fluid

“…When comparing 15 min vs. 12 h post-ALF exposure, some PIMs/LM/ManLAM biosynthesisassociated genes decreased their expression (pmmA, whiB2, pimF, pimA) while others increased (manB, pimB, embC) (Fig 2 and Table 2). This suggests a temporal and dynamic adaptation of M.tb's cell envelope components in response to ALF, in agreement with previous reports showing cell envelope remodeling of M.tb during infection and in response to different environmental conditions [33,34,[38][39][40][41][42][43]. pmmB expression was too low to be detected by our qPCR assay at either timepoints tested, thus no log2 fold changes are shown.…”

Host- and Age-Dependent Transcriptional Changes in Mycobacterium tuberculosis Cell Envelope Biosynthesis Genes after Exposure to Human Alveolar Lining Fluid

“…Other PIMs/LM/ManLAM biosynthesis-associated genes slightly decreased (ppm1 and pimF), while others increased (manA and embC) (Table 2). Although most of the changes are not significant, the results suggest certain temporal and dynamic adaptation of M.tb's cell envelope components in response to ALF, in agreement with previous reports showing cell envelope remodeling of M.tb during infection and in response to different environmental conditions [26,27,[35][36][37][38][39][40]. pmmB expression was too low to be detected by our qPCR assay at either timepoints tested, thus no fold changes are shown.…”

Lipid Droplets, the Central Hub Integrating Cell Metabolism and the Immune System

“…As a highly successful intracellular pathogen, M.tb can tolerate harsh conditions and reside long-term within its host by refining its metabolism. Studies conducted over the past 60 years have clearly shown that M.tb relies on fatty acids and cholesterol as important nutrients during infection ( Bloch and Segal, 1956 ; Chang and Guan, 2021 ). There are two types of growth behavior in bacteria: diauxic and coutilization of carbon sources.…”