Understanding Metabolic Regulation Between Host and Pathogens: New Opportunities for the Development of Improved Therapeutic Strategies Against Mycobacterium tuberculosis Infection

Abstract

Mycobacterium tuberculosis (Mtb) causes chronic granulomatous lung disease in humans. Recently, novel strategies such as host-directed therapeutics and adjunctive therapies that enhance the effect of existing antibiotics have emerged to better control Mtb infection. Recent advances in understanding the metabolic interplay between host immune cells and pathogens have provided new insights into how their interactions ultimately influence disease outcomes and antibiotic-treatment efficacy. In this review, we describe how metabolic cascades in immune environments and relevant metabolites produced from immune cells during Mtb infection play critical roles in the progression of diseases and induction of anti-Mtb protective immunity. In addition, we introduce how metabolic alterations in Mtb itself can lead to the development of persister cells that are resistant to host immunity and can eventually evade antibiotic attacks. Further understanding of the metabolic link between host cells and Mtb may contribute to not only the prevention of Mtb persister development but also the optimization of host anti-Mtb immunity together with enhanced efficacy of existing antibiotics. Overall, this review highlights novel approaches to improve and develop host-mediated therapeutic strategies against Mtb infection by restoring and switching pathogen-favoring metabolic conditions with host-favoring conditions.

Proteomic analysis of liver tissue revealsAeromonas hydrophilainfection mediated modulation of host metabolic pathways inLabeo rohita

“…Succinate accumulation also leads to the generation mROS and NO and can stabilise hypoxia-inducible factor 1-alpha (HIF-1α). Activated HIF-1α further promotes the glycolytic pathway and lactate production and causes inflammation by positively regulating the glycolytic genes and IL-1β expression (52,59). In our study, Lactate dehydrogenase enzyme (Ldha) has been found to show enriched expression in the Ah infected group (AH group).…”

“…In our study, Lactate dehydrogenase enzyme (Ldha) has been found to show enriched expression in the Ah infected group (AH group). During this reprogramming, mitochondrial electron transport chain (ETC) is highly disturbed (52). In our study, we observed dysregulation of many proteins involved in ETC and OXPHOS.…”

“…In Mtb infections, glycolytic reprogramming of M1 macrophages has been associated with two breaks in the tricarboxylic acid cycle (TCA cycle) and suppression of part of the electron transport chain (ETC) in the mitochondria. Breaks in TCA cycle includes the downregulation of two important enzymes i.e., Succinate dehydrogenase (SDH) and isocitrate dehydrogenase (IDH) that favours the build-up of Citrate and Succinate (52,53).…”

“…The enzyme Succinyl ligase also known as Succinate synthase converts succinyl-CoA to Succinate and free coenzyme A. The downstream metabolite of Citrate (Itaconate) inhibits Succinate dehydrogenase (SDH) activity that again leads to an increase in Succinate (52). Both Citrate and Succinate have been reported to be involved in pro-inflammatory immune functions in macrophages.…”

Host Immune-Metabolic Adaptations Upon Mycobacterial Infections and Associated Co-Morbidities

“…For instance, Ahr -/mice were unable to control M.tb H37Rv infection (212). Excellent recent reviews have further covered the potential intervention of metabolic pathways for HDT against TB (213)(214)(215)(216).…”