PUBLICATION

mTOR-regulated mitochondrial metabolism limits mycobacterium-induced cytotoxicity

Authors
Pagán, A.J., Lee, L.J., Edwards-Hicks, J., Moens, C.B., Tobin, D.M., Busch-Nentwich, E.M., Pearce, E.L., Ramakrishnan, L.
ID
ZDB-PUB-220920-7
Date
2022
Source
Cell   185(20): 3720-3738.e13 (Journal)
Registered Authors
Busch-Nentwich, Elisabeth, Moens, Cecilia, Ramakrishnan, Lalita, Tobin, David
Keywords
ESAT-6 mitotoxicity, Mycobacterium marinum, Mycobacterium tuberculosis, granuloma necrosis, mTOR, macrophage death, mitochondrial metabolism, oxidative phosphorylation, tuberculosis, zebrafish TB model
MeSH Terms
  • Tuberculosis*
  • Mycobacterium tuberculosis*/metabolism
  • Mycobacterium marinum*
  • TOR Serine-Threonine Kinases/metabolism
  • Zebrafish
  • Animals
(all 6)
PubMed
36103894 Full text @ Cell
Abstract
Necrosis of macrophages in the granuloma, the hallmark immunological structure of tuberculosis, is a major pathogenic event that increases host susceptibility. Through a zebrafish forward genetic screen, we identified the mTOR kinase, a master regulator of metabolism, as an early host resistance factor in tuberculosis. We found that mTOR complex 1 protects macrophages from mycobacterium-induced death by enabling infection-induced increases in mitochondrial energy metabolism fueled by glycolysis. These metabolic adaptations are required to prevent mitochondrial damage and death caused by the secreted mycobacterial virulence determinant ESAT-6. Thus, the host can effectively counter this early critical mycobacterial virulence mechanism simply by regulating energy metabolism, thereby allowing pathogen-specific immune mechanisms time to develop. Our findings may explain why Mycobacterium tuberculosis, albeit humanity's most lethal pathogen, is successful in only a minority of infected individuals.
Genes / Markers
Figures
Figure Gallery (11 images) / 2
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Expression
Phenotype
Fish Conditions Stage Phenotype Figure
ABbiological treatment: Mycobacterium marinum M, chemical treatment by environment: sirolimusLong-pec to Day 6
ABbiological treatment: Mycobacterium marinum M, chemical treatment by environment: torin 1Long-pec to Day 6
AB + CRISPR1-ndufaf1 + CRISPR2-ndufaf1 + CRISPR3-ndufaf1 + CRISPR4-ndufaf1biological treatment: Mycobacterium marinum MLong-pec to Days 7-13
mtorfh178/fh178biological treatment: Mycobacterium marinum MLong-pec to Day 6
mtorfh178/fh178; w200Tg/w200Tgstandard conditionsLong-pec to Day 4
mtorfh178/fh178; w200Tg/w200Tgbiological treatment: Mycobacterium marinum MLong-pec to Day 4
mtorfh178/fh178; w200Tg/w200Tgbiological treatment: Mycobacterium marinum MLong-pec to Day 6
mtorfh178/fh178; w200Tg/w200Tgbiological treatment: Mycobacterium marinum MLong-pec to Day 6
mtorfh178/fh178; w200Tg/w200Tgbiological treatment: Mycobacterium marinum MLong-pec to Day 6
mtorfh178/fh178; w200Tg/w200Tgbiological treatment: Mycobacterium marinum MLong-pec to Day 6
1 - 10 of 44
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Mutations / Transgenics
Allele Construct Type Affected Genomic Region
cu34TgTransgenic Insertion
    fh178
      Unknown
      nz117TgTransgenic Insertion
        sa11164
          Point Mutation
          sa11537
            Point Mutation
            sa15967
              Point Mutation
              sa16755
                Point Mutation
                sa18403
                  Point Mutation
                  sa24272
                    Point Mutation
                    sa35634
                      Point Mutation
                      1 - 10 of 16
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                      Human Disease / Model
                      No data available
                      Sequence Targeting Reagents
                      Fish
                      Antibodies
                      Orthology
                      Engineered Foreign Genes
                      Marker Marker Type Name
                      CeruleanEFGCerulean
                      EGFPEFGEGFP
                      EYFPEFGEYFP
                      GFPEFGGFP
                      NTREFGNTR
                      TomatoEFGTomato
                      YFPEFGYFP
                      1 - 7 of 7
                      Show
                      Mapping