Mycobacteria and Autophagy: Many Questions and Few Answers

Liang, Min; Habib, Zeshan; Sakamoto, Kaori; Chen, Xi; Cao, Gang

doi:10.21775/cimb.021.063

Cited by 8 publications

(7 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These data indicate that aerosolised lactate delivered to the lungs may hold potential as a host-directed therapy for active pulmonary TB, where there is both ongoing mycobacterial replication and destruction of pulmonary tissue due to an unchecked proinflammatory response. Mtb blocks autophagic flux as a method of subverting host defence (50,51). Our data indicates that lactate promotes autophagy which contributes to increased Mtb killing in human MDM.…”

Section: Discussionmentioning

confidence: 72%

Lactate Alters Metabolism in Human Macrophages and Improves Their Ability to Kill Mycobacterium tuberculosis

et al. 2021

View full text Add to dashboard Cite

In order to mount an appropriate immune response to infection, the macrophage must alter its metabolism by increasing aerobic glycolysis and concomitantly decreasing oxidative phosphorylation; a process known as the Warburg effect. Consequently, lactate, the end-product of glycolysis, accumulates in the extracellular environment. The subsequent effect of lactate on surrounding macrophages is poorly understood. Mycobacterium tuberculosis (Mtb), the causative organism of Tuberculosis (TB), is phagocytosed by macrophages in the airways. Mtb infected macrophages upregulate aerobic glycolysis and effector functions to try to kill the bacteria. Our lab has previously shown that human macrophages produce lactate in response to infection with Mtb. Although lactate has largely been considered a waste product of aerobic glycolysis, we hypothesised that the presence of extracellular lactate would impact subsequent immunometabolic responses and modulate macrophage function. We demonstrate that the presence of exogenous lactate has an immediate effect on the cellular metabolism of resting human macrophages; causing a decrease in extracellular acidification rate (ECAR; analogous to the rate of glycolysis) and an increase in the oxygen consumption rate (OCR; analogous to oxidative phosphorylation). When lactate-treated macrophages were stimulated with Mtb or LPS, glycolysis proceeds to increase immediately upon stimulation but oxidative phosphorylation remains stable compared with untreated cells that display a decrease in OCR. This resulted in a significantly reduced ECAR/OCR ratio early in response to stimulation. Since altered metabolism is intrinsically linked to macrophage function, we examined the effect of lactate on macrophage cytokine production and ability to kill Mtb. Lactate significantly reduced the concentrations of TNF and IL-1β produced by human macrophages in response to Mtb but did not alter IL-10 and IL-6 production. In addition, lactate significantly improved bacillary clearance in human macrophages infected with Mtb, through a mechanism that is, at least in part, mediated by promoting autophagy. These data indicate that lactate, the product of glycolysis, has a negative feedback effect on macrophages resulting in an attenuated glycolytic shift upon subsequent stimulation and reduced pro-inflammatory cytokine production. Interestingly, this pro-resolution effect of lactate is associated with increased capacity to kill Mtb.

show abstract

Section: Discussionmentioning

confidence: 72%

Lactate Alters Metabolism in Human Macrophages and Improves Their Ability to Kill Mycobacterium tuberculosis

et al. 2021

View full text Add to dashboard Cite

show abstract

“…S1 ). Autophagy is one of the most important mechanisms for macrophages to inhibit the growth of Mtb ( 6 , 7 ). Therefore, the status of BBM on autophagy induction was investigated.…”

Section: Resultsmentioning

confidence: 99%

Berbamine promotes macrophage autophagy to clear Mycobacterium tuberculosis by regulating the ROS/Ca ²⁺ axis

Zhang

Zhou

et al. 2023

mBio

View full text Add to dashboard Cite

Drug-resistant tuberculosis (TB) poses a major threat to global TB control; consequently, there is an urgent need to develop novel anti-TB drugs or strategies. Host-directed therapy (HDT) is emerging as an effective treatment strategy, especially for drug-resistant TB. This study evaluated the effects of berbamine (BBM), a bisbenzylisoquinoline alkaloid, on mycobacterial growth in macrophages. BBM inhibited intracellular Mycobacterium tuberculosis (Mtb) growth by promoting autophagy and silencing ATG5, partially abolishing the inhibitory effect. In addition, BBM increased intracellular reactive oxygen species (ROS), while the antioxidant N -acetyl-L-cysteine (NAC) abolished BBM-induced autophagy and the ability to inhibit Mtb survival. Furthermore, the increased intracellular Ca 2+ concentration induced by BBM was regulated by ROS, and BAPTA-AM, an intracellular Ca 2+ -chelating agent, could block ROS-mediated autophagy and Mtb clearance. Finally, BBM could inhibit the survival of drug-resistant Mtb. Collectively, these findings provide evidence that BBM, a Food and Drug Administration (FDA)–approved drug, could effectively clear drug-sensitive and -resistant Mtb through regulating ROS/Ca 2+ axis-mediated autophagy and has potential as an HDT candidate for TB therapy. IMPORTANCE It is urgent to develop novel treatment strategies against drug-resistant TB, and HDT provides a promising approach to fight drug-resistant TB by repurposing old drugs. Our studies demonstrate, for the first time, that BBM, an FDA-approved drug, not only potently inhibits intracellular drug-sensitive Mtb growth but also restricts drug-resistant Mtb by promoting macrophage autophagy. Mechanistically, BBM activates macrophage autophagy by regulating the ROS/Ca 2+ axis. In conclusion, BBM could be considered as an HDT candidate and may contribute to improving the outcomes or shortening the treatment course of drug-resistant TB.

show abstract

“…This gene is autophagy-related 10 homolog ATG10 that functions to mediate interactions between other autophagy related proteins that together function to induce and carryout autophagic functions. Autophagy is a process where host cells recycle organelles, but is also heavily involved in the innate immune defense against a variety of pathogens (34,94,95). The importance of autophagy specifically in mycobacterial infection has been identified, where inducing autophagy is shown to reduce mycobacterial persistence in cell culture (70,73,96,97).…”

Section: Genome Wide Association Studiesmentioning

confidence: 99%

“…Although the role of autophagy and vitamin D signaling in JD is not well-studied, the influence of both pathways and polymorphisms on M. tuberculosis infection is well-documented. Both pathways are interconnected and are shown to be necessary for pathogen clearance, where polymorphisms in autophagy machinery or VDR genes predispose hosts to disease (95,117,118). Interestingly, Pant et al (92) identified significance of ATG10 with QTL on bovine chromosome 7 which participates in formation of the autophagy machinery (92,119).…”

Section: Functional Mechanisms Of Proposed Candidate Genes In Map Infectionmentioning

confidence: 99%

The Paratuberculosis Paradigm Examined: A Review of Host Genetic Resistance and Innate Immune Fitness in Mycobacterium avium subsp. Paratuberculosis Infection

Pelzer

Sriranganathan

2021

Front. Vet. Sci.

View full text Add to dashboard Cite

Paratuberculosis, or Johne's Disease (JD) is a debilitating chronic enteritis mainly affecting ruminants caused by Mycobacterium avium subsp. paratuberculosis (MAP). This organism causes worldwide economic losses to the livestock industry, and is of public health importance due to the potential zoonotic risk between MAP and Crohn's disease (CD) in humans. Without economical treatments, or a vaccine capable of preventing infection without causing cross-reactions with bovine tuberculosis, test-and-cull methods for disease control are imperative. Unfortunately, difficulties in diagnostics and long subclinical stage hinder adequate control and is further complicated by variation in MAP exposure outcome. Interestingly, the majority of infections result in asymptomatic presentation and never progress to clinical disease. One contributing factor is host genetics, where polymorphisms in innate immune genes have been found to influence resistance and susceptibility to disease. Candidate genes identified across studies overlap with those found in CD and tuberculosis including; Solute carrier family 11 member 1 gene (SLC11A1), Nucleotide-binding-oligomerization domain containing gene 2 (NOD2), Major histocompatibility complex type II (MHC-II), and Toll-like receptor (TLR) genes. This review will highlight evidence supporting the vital role of these genes in MAP infection outcome, associated challenges, and implications for the future of JD research.

show abstract

Mycobacteria and Autophagy: Many Questions and Few Answers

Cited by 8 publications

References 35 publications

Lactate Alters Metabolism in Human Macrophages and Improves Their Ability to Kill Mycobacterium tuberculosis

Lactate Alters Metabolism in Human Macrophages and Improves Their Ability to Kill Mycobacterium tuberculosis

Berbamine promotes macrophage autophagy to clear Mycobacterium tuberculosis by regulating the ROS/Ca ²⁺ axis

The Paratuberculosis Paradigm Examined: A Review of Host Genetic Resistance and Innate Immune Fitness in Mycobacterium avium subsp. Paratuberculosis Infection

Contact Info

Product

Resources

About

Mycobacteria and Autophagy: Many Questions and Few Answers

Cited by 8 publications

References 35 publications

Lactate Alters Metabolism in Human Macrophages and Improves Their Ability to Kill Mycobacterium tuberculosis

Lactate Alters Metabolism in Human Macrophages and Improves Their Ability to Kill Mycobacterium tuberculosis

Berbamine promotes macrophage autophagy to clear Mycobacterium tuberculosis by regulating the ROS/Ca 2+ axis

The Paratuberculosis Paradigm Examined: A Review of Host Genetic Resistance and Innate Immune Fitness in Mycobacterium avium subsp. Paratuberculosis Infection

Contact Info

Product

Resources

About

Berbamine promotes macrophage autophagy to clear Mycobacterium tuberculosis by regulating the ROS/Ca ²⁺ axis