Characterizing virulence-specific perturbations in the mitochondrial function of macrophages infected with mycobacterium tuberculosis

Jamwal, Shilpa; Midha, Mukul K.; Verma, Hirdya Narain; Basu, Atanu; Rao, Kanury V. S.; Manivel, Venkatasamy

doi:10.1038/srep01328

Cited by 74 publications

(91 citation statements)

References 59 publications

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“…However, it is unclear which mechanisms Mtb uses to alter host cell death modes in its favor (Moraco and Kornfeld, 2014). In this study, we demonstrated that the Mtb toxin TNT damages mitochondria, a key event in the necrotic cell death of Mtb-infected macrophages (Chen et al, 2006; Duan et al, 2002; Jamwal et al, 2013). The observed mitochondrial damage is a consequence of the NAD + glycohydrolase activity of TNT and does not require a direct interaction of TNT with mitochondria, in contrast to other Mtb proteins associated with mitochondria (Cadieux et al, 2011; Sohn et al, 2011).…”

Section: Discussionmentioning

confidence: 75%

NAD+ Depletion Triggers Macrophage Necroptosis, a Cell Death Pathway Exploited by Mycobacterium tuberculosis

et al. 2018

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SUMMARY Mycobacterium tuberculosis (Mtb) kills infected macrophages by inhibiting apoptosis and promoting necrosis. The tuberculosis necrotizing toxin (TNT) is a secreted nicotinamide adenine dinucleotide (NAD+) glycohydrolase that induces necrosis in infected macrophages. Here, we show that NAD+ depletion by TNT activates RIPK3 and MLKL, key mediators of necroptosis. Notably, Mtb bypasses the canonical necroptosis pathway since neither TNF-α nor RIPK1 are required for macrophage death. Macrophage necroptosis is associated with depolarized mitochondria and impaired ATP synthesis, known hallmarks of Mtb-induced cell death. These results identify TNT as the main trigger of necroptosis in Mtb-infected macrophages. Surprisingly, NAD+ depletion itself was sufficient to trigger necroptosis in a RIPK3- and MLKL-dependent manner by inhibiting the NAD+ salvage pathway in THP-1 cells or by TNT expression in Jurkat T cells. These findings suggest avenues for host-directed therapies to treat tuberculosis and other infectious and age-related diseases in which NAD+ deficiency is a pathological factor.

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Section: Discussionmentioning

confidence: 75%

NAD+ Depletion Triggers Macrophage Necroptosis, a Cell Death Pathway Exploited by Mycobacterium tuberculosis

et al. 2018

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“…It is found that mitochondria in M. tuberculosis H37Rv-infected cells displayed robust activity with increased membrane potential and ATP synthesis [33]. Ultrastructural changes in the mitochondria and mitochondrial clustering are also observed in the M. tuberculosis H37Rv infected cells [33].…”

Section: Resultsmentioning

confidence: 99%

Stringent homology-based prediction of H. sapiens-M. tuberculosis H37Rv protein-protein interactions

et al. 2014

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BackgroundH. sapiens-M. tuberculosis H37Rv protein-protein interaction (PPI) data are essential for understanding the infection mechanism of the formidable pathogen M. tuberculosis H37Rv. Computational prediction is an important strategy to fill the gap in experimental H. sapiens-M. tuberculosis H37Rv PPI data. Homology-based prediction is frequently used in predicting both intra-species and inter-species PPIs. However, some limitations are not properly resolved in several published works that predict eukaryote-prokaryote inter-species PPIs using intra-species template PPIs.ResultsWe develop a stringent homology-based prediction approach by taking into account (i) differences between eukaryotic and prokaryotic proteins and (ii) differences between inter-species and intra-species PPI interfaces. We compare our stringent homology-based approach to a conventional homology-based approach for predicting host-pathogen PPIs, based on cellular compartment distribution analysis, disease gene list enrichment analysis, pathway enrichment analysis and functional category enrichment analysis. These analyses support the validity of our prediction result, and clearly show that our approach has better performance in predicting H. sapiens-M. tuberculosis H37Rv PPIs. Using our stringent homology-based approach, we have predicted a set of highly plausible H. sapiens-M. tuberculosis H37Rv PPIs which might be useful for many of related studies. Based on our analysis of the H. sapiens-M. tuberculosis H37Rv PPI network predicted by our stringent homology-based approach, we have discovered several interesting properties which are reported here for the first time. We find that both host proteins and pathogen proteins involved in the host-pathogen PPIs tend to be hubs in their own intra-species PPI network. Also, both host and pathogen proteins involved in host-pathogen PPIs tend to have longer primary sequence, tend to have more domains, tend to be more hydrophilic, etc. And the protein domains from both host and pathogen proteins involved in host-pathogen PPIs tend to have lower charge, and tend to be more hydrophilic.ConclusionsOur stringent homology-based prediction approach provides a better strategy in predicting PPIs between eukaryotic hosts and prokaryotic pathogens than a conventional homology-based approach. The properties we have observed from the predicted H. sapiens-M. tuberculosis H37Rv PPI network are useful for understanding inter-species host-pathogen PPI networks and provide novel insights for host-pathogen interaction studies.ReviewersThis article was reviewed by Michael Gromiha, Narayanaswamy Srinivasan and Thomas Dandekar.

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“…For example, macrophages react to some Mycobacterium tuberculosis strains by lowering the Dcm and iATP (23) and by inducing inflammasome activation and IL-1b production, ultimately promoting bacterial killing (24). Several intracellular bacteria or viruses reduce iATP levels (25).…”

Section: Discussionmentioning

confidence: 99%

Intracellular ATP Decrease Mediates NLRP3 Inflammasome Activation upon Nigericin and Crystal Stimulation

Nomura

Tamura

et al. 2015

The Journal of Immunology

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Activation of the nucleotide-binding oligomerization domain–like receptor family, pyrin domain–containing 3 (NLRP3) inflammasome initiates an inflammatory response, which is associated with host defense against pathogens and the progression of chronic inflammatory diseases such as gout and atherosclerosis. The NLRP3 inflammasome mediates caspase-1 activation and subsequent IL-1β processing in response to various stimuli, including extracellular ATP, although the roles of intracellular ATP (iATP) in NLRP3 activation remain unclear. In this study, we found that in activated macrophages artificial reduction of iATP by 2-deoxyglucose, a glycolysis inhibitor, caused mitochondrial membrane depolarization, leading to IL-1β secretion via NLRP3 and caspase-1 activation. Additionally, the NLRP3 activators nigericin and monosodium urate crystals lowered iATP through K+- and Ca2+-mediated mitochondrial dysfunction, suggesting a feedback loop between iATP loss and lowering of mitochondrial membrane potential. These results demonstrate the fundamental roles of iATP in the maintenance of mitochondrial function and regulation of IL-1β secretion, and they suggest that maintenance of the intracellular ATP pools could be a strategy for countering NLRP3-mediated inflammation.

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Characterizing virulence-specific perturbations in the mitochondrial function of macrophages infected with mycobacterium tuberculosis

Cited by 74 publications

References 59 publications

NAD+ Depletion Triggers Macrophage Necroptosis, a Cell Death Pathway Exploited by Mycobacterium tuberculosis

NAD+ Depletion Triggers Macrophage Necroptosis, a Cell Death Pathway Exploited by Mycobacterium tuberculosis

Stringent homology-based prediction of H. sapiens-M. tuberculosis H37Rv protein-protein interactions

Intracellular ATP Decrease Mediates NLRP3 Inflammasome Activation upon Nigericin and Crystal Stimulation

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