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1.
Proc Natl Acad Sci U S A ; 120(7): e2217673120, 2023 02 14.
Article in English | MEDLINE | ID: mdl-36745788

ABSTRACT

Biallelic mutations in the glucocerebrosidase (GBA1) gene cause Gaucher disease, characterized by lysosomal accumulation of glucosylceramide and glucosylsphingosine in macrophages. Gaucher and other lysosomal diseases occur with high frequency in Ashkenazi Jews. It has been proposed that the underlying mutations confer a selective advantage, in particular conferring protection against tuberculosis. Here, using a zebrafish Gaucher disease model, we find that the mutation GBA1 N370S, predominant among Ashkenazi Jews, increases resistance to tuberculosis through the microbicidal activity of glucosylsphingosine in macrophage lysosomes. Consistent with lysosomal accumulation occurring only in homozygotes, heterozygotes remain susceptible to tuberculosis. Thus, our findings reveal a mechanistic basis for protection against tuberculosis by GBA1 N370S and provide biological plausibility for its selection if the relatively mild deleterious effects in homozygotes were offset by significant protection against tuberculosis, a rampant killer of the young in Europe through the Middle Ages into the 19th century.


Subject(s)
Gaucher Disease , Tuberculosis , Animals , Gaucher Disease/genetics , Zebrafish/genetics , Glucosylceramidase/genetics , Mutation , Tuberculosis/genetics , Tuberculosis/prevention & control
2.
Science ; 376(6600): eabh2841, 2022 06 24.
Article in English | MEDLINE | ID: mdl-35737799

ABSTRACT

Tumor necrosis factor (TNF) is a critical host resistance factor against tuberculosis. However, excess TNF produces susceptibility by increasing mitochondrial reactive oxygen species (mROS), which initiate a signaling cascade to cause pathogenic necrosis of mycobacterium-infected macrophages. In zebrafish, we identified the mechanism of TNF-induced mROS in tuberculosis. Excess TNF in mycobacterium-infected macrophages elevates mROS production by reverse electron transport (RET) through complex I. TNF-activated cellular glutamine uptake leads to an increased concentration of succinate, a Krebs cycle intermediate. Oxidation of this elevated succinate by complex II drives RET, thereby generating the mROS superoxide at complex I. The complex I inhibitor metformin, a widely used antidiabetic drug, prevents TNF-induced mROS and necrosis of Mycobacterium tuberculosis-infected zebrafish and human macrophages; metformin may therefore be useful in tuberculosis therapy.


Subject(s)
Electron Transport Complex I , Macrophages , Metformin , Mycobacterium tuberculosis , Reactive Oxygen Species , Tuberculosis , Tumor Necrosis Factor-alpha , Animals , Citric Acid Cycle/drug effects , Electron Transport , Electron Transport Complex I/antagonists & inhibitors , Electron Transport Complex I/metabolism , Humans , Macrophages/metabolism , Macrophages/microbiology , Macrophages/pathology , Metformin/pharmacology , Mycobacterium tuberculosis/metabolism , Necrosis , Reactive Oxygen Species/metabolism , Succinic Acid/metabolism , Tuberculosis/metabolism , Tuberculosis/microbiology , Tuberculosis/pathology , Tumor Necrosis Factor-alpha/metabolism , Zebrafish
3.
Proc Natl Acad Sci U S A ; 118(10)2021 03 09.
Article in English | MEDLINE | ID: mdl-33658385

ABSTRACT

Adjunctive treatment with antiinflammatory corticosteroids like dexamethasone increases survival in tuberculosis meningitis. Dexamethasone responsiveness associates with a C/T variant in Leukotriene A4 Hydrolase (LTA4H), which regulates expression of the proinflammatory mediator leukotriene B4 (LTB4). TT homozygotes, with increased expression of LTA4H, have the highest survival when treated with dexamethasone and the lowest survival without. While the T allele is present in only a minority of the world's population, corticosteroids confer modest survival benefit worldwide. Using Bayesian methods, we examined how pretreatment levels of cerebrospinal fluid proinflammatory cytokines affect survival in dexamethasone-treated tuberculous meningitis. LTA4H TT homozygosity was associated with global cytokine increases, including tumor necrosis factor. Association between higher cytokine levels and survival extended to non-TT patients, suggesting that other genetic variants may also induce dexamethasone-responsive pathological inflammation. These findings warrant studies that tailor dexamethasone therapy to pretreatment cerebrospinal fluid cytokine concentrations, while searching for additional genetic loci shaping the inflammatory milieu.


Subject(s)
Cytokines/cerebrospinal fluid , Dexamethasone/administration & dosage , Epoxide Hydrolases/genetics , Genetic Variation , Tuberculosis, Meningeal , Disease-Free Survival , Female , Humans , Male , Middle Aged , Predictive Value of Tests , Survival Rate , Tuberculosis, Meningeal/cerebrospinal fluid , Tuberculosis, Meningeal/drug therapy , Tuberculosis, Meningeal/genetics , Tuberculosis, Meningeal/mortality
4.
Cell ; 178(6): 1344-1361.e11, 2019 09 05.
Article in English | MEDLINE | ID: mdl-31474371

ABSTRACT

Necrosis of infected macrophages constitutes a critical pathogenetic event in tuberculosis by releasing mycobacteria into the growth-permissive extracellular environment. In zebrafish infected with Mycobacterium marinum or Mycobacterium tuberculosis, excess tumor necrosis factor triggers programmed necrosis of infected macrophages through the production of mitochondrial reactive oxygen species (ROS) and the participation of cyclophilin D, a component of the mitochondrial permeability transition pore. Here, we show that this necrosis pathway is not mitochondrion-intrinsic but results from an inter-organellar circuit initiating and culminating in the mitochondrion. Mitochondrial ROS induce production of lysosomal ceramide that ultimately activates the cytosolic protein BAX. BAX promotes calcium flow from the endoplasmic reticulum into the mitochondrion through ryanodine receptors, and the resultant mitochondrial calcium overload triggers cyclophilin-D-mediated necrosis. We identify ryanodine receptors and plasma membrane L-type calcium channels as druggable targets to intercept mitochondrial calcium overload and necrosis of mycobacterium-infected zebrafish and human macrophages.


Subject(s)
Macrophages/microbiology , Macrophages/pathology , Mitochondria/metabolism , Mycobacterium Infections, Nontuberculous/metabolism , Tuberculosis/immunology , Tuberculosis/pathology , Tumor Necrosis Factor-alpha/metabolism , Animals , Apoptosis , Calcium/metabolism , Endoplasmic Reticulum/microbiology , Humans , Lysosomes/microbiology , Membrane Potential, Mitochondrial , Mycobacterium Infections, Nontuberculous/pathology , Mycobacterium marinum , Mycobacterium tuberculosis , Necrosis , Reactive Oxygen Species/metabolism , THP-1 Cells , Zebrafish
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