Quantitative Lipid Droplet Proteomics Reveals <i>Mycobacterium tuberculosis</i> Induced Alterations in Macrophage Response to Infection

Menon, Dilip; Singh, K. C.; Pinto, Sneha M.; Nandy, Aditya; Jaisinghani, Neetika; Kutum, Rintu; Dash, Debasis; Prasad, T. S. Keshava; Gandotra, Sheetal

doi:10.1021/acsinfecdis.8b00301

Cited by 38 publications

(26 citation statements)

References 42 publications

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“…These proteins include those of protein synthesis, lipid metabolism and vescicle trafiicking, which were thought to promote increased mobilization of lipids. The role of secreted proteins in the modulation of the proteome of lipid droplets, for instance, the role of LipY has been discussed (Menon et al, 2019 ). Given the opposing schools of thought that the lipid droplets are host induced or Mtb -induced, and the distinct signaling events in both cases, it appears that the lipid droplets are complex and dynamic entities that are modulated by Mtb by rewiring the immunometabolism of the host with IFN-γ driven lipid body in M1 state to IL-10 driven lipid droplets in M2 state that is accessible to Mtb following a change in proteomic composition.…”

Section: Mycobacterium Tuberculosis Infection Reallocates MImentioning

confidence: 99%

Mycobacterial Control of Host Mitochondria: Bioenergetic and Metabolic Changes Shaping Cell Fate and Infection Outcome

Mohareer

Medikonda

Vadankula

et al. 2020

Front. Cell. Infect. Microbiol.

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Mitochondria, are undoubtedly critical organelle of a eukaryotic cell, which provide energy and offer a platform for most of the cellular signaling pathways that decide cell fate. The role of mitochondria in immune-metabolism is now emerging as a crucial process governing several pathological states, including infection, cancer, and diabetes. Mitochondria have therefore been a vulnerable target for several bacterial and viral pathogens to control host machinery for their survival, replication, and dissemination. Mycobacterium tuberculosis, a highly successful human pathogen, persists inside alveolar macrophages at the primary infection site, applying several strategies to circumvent macrophage defenses, including control of host mitochondria. The infection perse and specific mycobacterial factors that enter the host mitochondrial milieu perturb mitochondrial dynamics and function by disturbing mitochondrial membrane potential, shifting bioenergetics parameters such as ATP and ROS, orienting the host cell fate and thereby infection outcome. In the present review, we attempt to integrate the available information and emerging dogmas to get a holistic view of Mycobacterium tuberculosis infection visa -vis mycobacterial factors that target host mitochondria and changes therein in terms of morphology, dynamics, proteomic, and bioenergetic alterations that lead to a differential cell fate and immune response determining the disease outcome. We also discuss critical host factors and processes that are overturned by Mycobacterium tuberculosis, such as cAMP-mediated signaling, redox homeostasis, and lipid droplet formation. Further, we also present alternate dogmas as well as the gaps and limitations in understanding some of the present research areas, which can be further explored by understanding some critical processes during Mycobacterium tuberculosis infection and the reasons thereof. Toward the end, we propose to have a set of guidelines for pursuing investigations to maintain uniformity in terms of early and late phase, MOI of infection, infection duration and incubation periods, the strain of mycobacteria, passage numbers, and so on, which all work as probable variables toward different readouts. Such a setup would, therefore, help in the smooth integration of information across laboratories toward a better understanding of the disease and possibilities of host-directed therapy.

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Section: Mycobacterium Tuberculosis Infection Reallocates MImentioning

confidence: 99%

Mycobacterial Control of Host Mitochondria: Bioenergetic and Metabolic Changes Shaping Cell Fate and Infection Outcome

Mohareer

Medikonda

Vadankula

et al. 2020

Front. Cell. Infect. Microbiol.

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“…This shows that both activation and inhibition of mTOR signaling can result in the formation of LDs. Whether this results in structurally distinct LDs with different immunological functions requires further study [103,131]. In this context it is interesting to note that M. leprae induces LDs that seem to mainly consist of cholesterol and cholesterol esters, while in M. tuberculosis infection LD formation is primarily the result of TAG accumulation [132].…”

Section: Lipid Dropletsmentioning

confidence: 99%

Pathogens MenTORing Macrophages and Dendritic Cells: Manipulation of mTOR and Cellular Metabolism to Promote Immune Escape

Nouwen

Everts

2020

Cells

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Myeloid cells, including macrophages and dendritic cells, represent an important first line of defense against infections. Upon recognition of pathogens, these cells undergo a metabolic reprogramming that supports their activation and ability to respond to the invading pathogens. An important metabolic regulator of these cells is mammalian target of rapamycin (mTOR). During infection, pathogens use host metabolic pathways to scavenge host nutrients, as well as target metabolic pathways for subversion of the host immune response that together facilitate pathogen survival. Given the pivotal role of mTOR in controlling metabolism and DC and macrophage function, pathogens have evolved strategies to target this pathway to manipulate these cells. This review seeks to discuss the most recent insights into how pathogens target DC and macrophage metabolism to subvert potential deleterious immune responses against them, by focusing on the metabolic pathways that are known to regulate and to be regulated by mTOR signaling including amino acid, lipid and carbohydrate metabolism, and autophagy.

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“…HILPDA is responsible for lipid accumulation as the cell slowly changes its metabolism towards low oxygen environments. Mtb has been known to adapt to a fatty-acid-rich environment of the cell [41]. It has also been experimentally proved that cellular organelles which store host lipids, are actively manipulated by Mtb during active TB [42].…”

Section: Discussionmentioning

confidence: 99%

lncRNA Mediated Hijacking of T-cell Hypoxia Response Pathway byMycobacterium tuberculosisPredicts Latent to Active Progression in Humans

Mehra

Kumar

Srivastava

et al. 2020

Preprint

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Cytosolic functions of Long non-coding RNAs including mRNA translation masking and sponging are major regulators of biological pathways. Formation of T cell-bounded hypoxic granuloma is a host immune defense for containing infected Mtb-macrophages. Our study exploits the mechanistic pathway of Mtb-induced HIF1A silencing by the antisense lncRNA-HIF1A-AS2 in T cells. Computational analysis of in-vitro T-cell stimulation assays in progressors(n=119) versus latent(n=221) tuberculosis patients revealed the role of lncRNA mediated disruption of hypoxia adaptation pathways in progressors.We found 291 upregulated and 227 downregulated lncRNAs that were correlated at mRNA level with HIF1A and HILPDA which are major players in hypoxia response. We also report novel lncRNA-AC010655 (AC010655.4 and AC010655.2) in cis with HILPDA, both of which contain binding sites for the BARX2 transcription factor, thus indicating a mechanistic role. Detailed comparison of infection with antigenic stimulation showed a non-random enrichment of lncRNAs in the cytoplasmic fraction of the cell in progressors. The lack of this pattern in non-progressors indicates the hijacking of the lncRNA dynamics by Mtb. The in-vitro manifestation of this response in the absence of granuloma indicates pre-programmed host-pathogen interaction between T-cells and Mtb regulated through lncRNAs, thus tipping this balance towards progression or containment of Mtb. Finally, we trained multiple machine learning classifiers for reliable prediction of latent to the active progression of patients, yielding a model to guide aggressive treatment.

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Quantitative Lipid Droplet Proteomics Reveals Mycobacterium tuberculosis Induced Alterations in Macrophage Response to Infection

Cited by 38 publications

References 42 publications

Mycobacterial Control of Host Mitochondria: Bioenergetic and Metabolic Changes Shaping Cell Fate and Infection Outcome

Mycobacterial Control of Host Mitochondria: Bioenergetic and Metabolic Changes Shaping Cell Fate and Infection Outcome

Pathogens MenTORing Macrophages and Dendritic Cells: Manipulation of mTOR and Cellular Metabolism to Promote Immune Escape

lncRNA Mediated Hijacking of T-cell Hypoxia Response Pathway byMycobacterium tuberculosisPredicts Latent to Active Progression in Humans

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