Pathogens MenTORing Macrophages and Dendritic Cells: Manipulation of mTOR and Cellular Metabolism to Promote Immune Escape
Abstract
1. Introduction
2. Direct Targeting of mTOR Complexes by Pathogens
3. Targeting of Amino Acid Metabolism by Pathogens
3.1. Tryptophan
3.2. L-Arginine
3.3. Asparagine
4. Targeting of Lipid Metabolism by Pathogens
4.1. Lipid Droplets
4.2. Membranes
5. Targeting of Carbohydrate Metabolism by Pathogens
6. Targeting of Other mTOR-Controlled Processes by Pathogens
6.1. Autophagy
6.2. Host Translation
6.3. Innate Cytokines
7. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Direct Targeting mTOR | ||
---|---|---|
Effect | Pathogen | References |
Induction of autophagy by secreting a rapamycin homolog and inhibiting mTOR leading to impaired human monocyte-derived DC function | B. malayi | [22] |
Cleavage of mTOR via the protease GP63 in B10R macrophages leading to decreased type I IFN production and expression of iNOS | L. major | [23] |
Relocating mTOR to maintain mTORC1 activation in HFFs and U373-MG cells | HCMV | [24,25] |
Sequestering of raptor and rictor in PMA differentiated THP-1 cells leading to mTOR relocalization and inhibition of cGAS-STING activation and induction of IRGs | Poxviruses (including VacV) | [28,29] |
Direct interaction with mTORC2 to modulate macrophage phenotype and migration (in this case PMA differentiated THP-1 cells) | HIV-1 | [30] |
Amino Acid Metabolism | ||
Effect | Pathogen | References |
Synthesize tryptophan thereby counteracting IDO depletion of tryptophan | M. tuberculosis, F. Tularensis, C. trachomatis | [9,41] |
Expresses a IL-10 homolog (cmvIL-10) that induces IDO in human monocyte-derived DCs | HCMV | [47,48] |
Induction of IDO in langerin negative dermal dendritic cells | HPV | [49] |
Induction of host arginases in mouse macrophages | Trypanosoma sps, Leishmania sps, T. gondii, S. typhimurium, H. pylori, S. pneumonia, C. albicans, M. tuberculosis and S. mansoni | [65,66,67,68,69,70] |
Expression of pathogen arginase | Leishmania sps, Plasmodium sps, C. albicans, S. mansoni and H. pylori | [65,71,72,73,74,75,76] |
Arginase 1 induction in CD33+ PBMCs mediates L-arginine depletion leading to mTOR inhibition and decreased IFNy production in co-cultured NK cells | HCV | [79] |
Depletion of L-arginine by expression of arginine deiminase modulates cytokine production and phenotype of human monocyte-derived DCs via the inhibition of mTORC1 | G. duodenalis | [80] |
Asparaginase expression leading to asparagine depletion and dampening of immune responses in T cells and macrophages (ANA-1 and RAW264.7 cells) | Expression: multiple pathogens including H. pylori and S. typhimurium Dampening immune response: S. typhimurium, Erwinia asparaginase | [88,89,90,91,92] [90,93] |
Lipid Metabolism | ||
Effect | Pathogen | References |
Induction of LD formation and PGE2 synthesis for successful replication and modulation of the immune (reduction of antigen-stimulated lymphocyte replication, reduction of killing ability infected cells) | T. cruzi, M. leprae, HMCV, HIV | [112,113,114,115,116,117,118] |
Active stimulation of LD formation via SseJ | S. Typhimurium | [104] |
Accumulation of LDs in pathogen vacuoles | C. pneumoniae, T. cruzi | [104] |
Upregulation COX-2 and PGE2 synthesis in RAW264.7 cells and murine BMDMs and BMDCs | S. typhimurium | [60,119] |
Production of PGE2 and accumulation of LDs increasing virulence | Human pathogenic fungi | [120,121,122] |
Induction of LDs to enhance replication efficiency and the assembly of nascent virions | Viruses, including HCV and Rotaviruses | [104,123] |
mTOR inhibition to induce autophagy of LDs to enhance replication efficiency | Flaviviruses, including Dengue | [124,125] |
Promoting mTORC1-dependent TAG accumulation in human macrophages that contributes to LD formation | M. tuberculosis, T. gondii | [102,126] |
Inducing LDs and PGE2 synthesis via autophagy in BALB/c macrophages | L. amazonensis | [129] |
Rapamycin induces LD formation | S. cerevisiae | [130] |
Reducing cholesterol levels at the plasma membrane of Vero cells which disrupts Jak-STAT signaling | WNV | [135] |
Altered CD40 signalosome in BALB/c derived peritoneal macrophages by depleting cholesterol leading to IL-10 production | L. major | [136] |
Carbohydrate Metabolism | ||
Effect | Pathogen | References |
Prevents glycolytic shift in primary macrophages by downregulating HIF1α | F. Tularensis | [143] |
Depleting intracellular glucose to inhibit glycolysis in murine BMDMs | S. Typhimurium | [144,145] |
Depleting extracellular glucose leading to the death of restimulated macrophages (murine BMDMs and PMA differentiated THP-1 cells) | C. albicans | [146] |
Promotion of glucose oxidation in murine BMDMs through activation of SIRT1, LKB1 and AMPK increasing survival and proliferation | L. infantum | [147] |
Promotes glycolysis (Warburg like metabolism) in human monocyte-derived macrophages | L. pneumophila | [149,150,151,152] |
Autophagy | ||
Effect | Pathogen | References |
Inhibition by stimulating the PI3K-Akt-mTOR pathway | Viruses in general | [160,161] |
Targeting AMPK, SIRT1 and LKB1 for degradation in murine BMDMs | S. typhimurium | [98] |
Activation of mTOR (via CagA) and inhibition of autophagy | H. pylori | [162] |
Induction of autophagy to increase sites of replication, to liberate nutrients and/or to protect host cell death | Flaviviruses (including Zika), coxsackievirus | [163,164,165,166] |
Induction of autophagy independent of mTOR which contributes to parasite growth. | T. gondii | [167,168] |
Inhibition of autophagy by stimulating mTOR early in infection in PMA differentiated THP-1 cells. Induction of autophagy during later stages of infection, regulated independent of mTOR. | L. donovani | [169] |
Inhibiting autophagy by stimulating mTOR to decrease cross-presentation and enhance spreading of infection. | HIV-1 | [170,171] |
Host Translation | ||
Effect | Pathogen | References |
Activates mTORC1 to promote translation of proteins for mitochondrial biogenesis and function, possibly to modulate the innate immune response (in BMDMs and PECs) | T. gondii | [177,178] |
Cleavage of mTOR via the protease GP63 in B10R macrophages to prevent IFN type I production and iNOS translation | L. major | [23] |
Mediates shut off of host translation which leads to a decreased translation of innate cytokines in U937 cells | HSV-1 | [179] |
Shut off of host translation to favor replication of own genome and to downregulate IFITM proteins | Viruses relying on IRES-dependent translation | [23,161,180,181,182,183] |
Innate Cytokines | ||
Effect | Pathogen | References |
Cell wall moieties induce the production of IL-10 via TLR2 and mTOR signaling in human PBMCs | S. aureus | [185] |
TLR2 and mTOR dependent IL-10 production in PMA differentiated THP-1 cells | L. donovani | [186] |
Rapamycin decreases IL-10 production in cornea of infected Balb/c mice | P. aeruginosa | [187] |
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Nouwen, L.V.; Everts, B. Pathogens MenTORing Macrophages and Dendritic Cells: Manipulation of mTOR and Cellular Metabolism to Promote Immune Escape. Cells 2020, 9, 161. https://doi.org/10.3390/cells9010161
Nouwen LV, Everts B. Pathogens MenTORing Macrophages and Dendritic Cells: Manipulation of mTOR and Cellular Metabolism to Promote Immune Escape. Cells. 2020; 9(1):161. https://doi.org/10.3390/cells9010161
Chicago/Turabian StyleNouwen, Lonneke V., and Bart Everts. 2020. "Pathogens MenTORing Macrophages and Dendritic Cells: Manipulation of mTOR and Cellular Metabolism to Promote Immune Escape" Cells 9, no. 1: 161. https://doi.org/10.3390/cells9010161
APA StyleNouwen, L. V., & Everts, B. (2020). Pathogens MenTORing Macrophages and Dendritic Cells: Manipulation of mTOR and Cellular Metabolism to Promote Immune Escape. Cells, 9(1), 161. https://doi.org/10.3390/cells9010161