Inhibition of the PI3K-Akt-mTOR signaling pathway in T lymphocytes in patients with active tuberculosis

Zhang, Xuexuan; Huang, Tseng-Chieng; Wu, Ying; Peng, WenGuang; Xie, Hanbin; Pan, Meichen; Zhou, Huanbin; Cai, Bin

doi:10.1016/j.ijid.2017.04.004

Cited by 32 publications

(27 citation statements)

References 20 publications

(25 reference statements)

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“…The phosphatidylinositol 3 kinase (PI3K)/Akt signaling is crucial for cell growth, proliferation, and differentiation. It has recently been demonstrated to play important roles in regulating immune responses in many cell types [ 14 – 16 ]; the involvement of PI3K/Akt signaling in the interaction between epithelial cells and macrophages therefore was examined. Intriguingly, the Mtb H37Rv-activated TLR signaling of U937-derived macrophage-like cells was almost completely abolished or inhibited by the addition of PI3K inhibitor LY294002 at final concentration of 100 μ M (Santa Cruz, Santa Cruz, CA, USA) as determined by an immunoblotting assay (Figures 4(a) and 4(b) ).…”

Section: Resultsmentioning

confidence: 99%

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Epithelial Cells Attenuate Toll-Like Receptor-Mediated Inflammatory Responses in Monocyte-Derived Macrophage-Like Cells to Mycobacterium tuberculosis by Modulating the PI3K/Akt/mTOR Signaling Pathway

Yang

Sun

et al. 2018

Mediators of Inflammation

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Both alveolar macrophages (AMs) and alveolar epithelial cells (AECs) are main targets of Mycobacterium tuberculosis (M. tuberculosis (Mtb)). Intercellular communications between mucosal AECs and AMs have important implications in cellular responses to exogenous insults. However, molecular mechanisms underpinning interactions responding to Mtb remain largely unknown. In this study, impacts of AECs on Toll-like receptor- (TLR-) mediated inflammatory responses of AMs to Mtb virulent strain H37Rv were interrogated using an air-liquid interface (ALI) coculture model of epithelial A549 cells and U937 monocyte-derived macrophage-like cells. Results showed that Mtb-activated TLR-mediated inflammatory responses in U937 cells were significantly alleviated when A549 cells were coinfected with H37Rv, in comparison with the infection of U937 cells alone. Mechanistically, PI3K/Akt/mTOR signaling was involved in the epithelial cell-modulated Mtb-activated TLR signaling. The epithelial cell-attenuated TLR signaling in U937s could be reversed by PI3K inhibitor LY294002 and mTOR inhibitor rapamycin, but not glycogen synthase kinase 3β inhibitor LiCl, suggesting that the epithelially modulated-TLR signaling in macrophages was in part caused by inhibiting the TLR-triggered PI3K/Akt/mTOR signaling pathway. Together, this study demonstrates that mucosal AEC-derived signals play an important role in modulating inflammatory responses of AMs to Mtb, which thus also offers an insight into cellular communications between AECs and AMs to Mtb infections.

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Section: Resultsmentioning

confidence: 99%

“…This cellular signaling has been suggested to have an important implication in the pathogenesis of tuberculosis. Indeed, the PI3K/Akt/mTOR signaling pathway was impaired in the T lymphocytes of patients with active tuberculosis [ 16 ]. It has been demonstrated that BCG could activate phosphorylation of Akt in host cells.…”

Section: Discussionmentioning

confidence: 99%

Epithelial Cells Attenuate Toll-Like Receptor-Mediated Inflammatory Responses in Monocyte-Derived Macrophage-Like Cells to Mycobacterium tuberculosis by Modulating the PI3K/Akt/mTOR Signaling Pathway

Yang

Sun

et al. 2018

Mediators of Inflammation

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“…Since mTOR signaling pathway regulates several cellular processes, including autophagy, that are linked to the host immune response to pathogens, it is an attractive target for developing/testing small molecules to modulate host immunity for better protection against infectious agents. Moreover, the peripheral blood mononuclear cells (PBMCs) and CD 4+ CD 25+ FoxP 3+ Treg cells isolated from active tuberculosis patients demonstrated mTOR inhibition during infection (Zhang et al, 2017 ). In contrast, mTOR activation, by deletion of Tsc1 in hematopoietic stem cells, induces accumulation CDK (cyclin-dependent kinase) inhibitors p16 ink4a , p19 Arf , p21 Cip1 leading to impaired hematopoietic system and decreased lymphopoiesis (Chen et al, 2009 ).…”

Section: Mtor Inhibitors As Potential Hdt For Tbmentioning

confidence: 99%

Harnessing the mTOR Pathway for Tuberculosis Treatment

Singh

Subbian

2018

Front. Microbiol.

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Tuberculosis (TB) remains as one of the leading killer infectious diseases of humans. At present, the standard therapeutic regimen to treat TB comprised of multiple antibiotics administered for a minimum of six months. Although these drugs are useful in controlling TB burden globally, they have not eliminated the disease. In addition, the lengthy duration of treatment with multiple drugs contributes to patient non-compliance that can result in the development of drug resistant strains (MDR and XDR) of Mycobacterium tuberculosis (Mtb), the causative agent of TB. Therefore, new and improved therapeutic strategies are urgently needed for effective control of TB worldwide. The intracellular survival of Mtb is regarded as a cumulative effect of the host immune response and the bacterial ability to resist or subvert this response. When the host innate defensive system is manipulated by Mtb for its survival and dissemination, the host develops disease conditions that are hard to overcome. The host intrinsic factors also contributes to the poor efficacy of anti-mycobacterial drugs and to the emergence of drug resistance. Hence, strengthening the immune repertoire involved in combating Mtb through host-directed therapeutics (HDT) can be one of the approaches for effective bacterial killing and clearance of infection/disease. Recently, more scientific research has been focused toward HDT strategies that empowers host cells for effective killing of Mtb, reduce the duration of treatment and/or alleviates the development of MDR/XDR, since Mtb cannot develop resistance against a drug that targets the host cell function. Autophagy is a conserved cellular process critical for maintaining cellular integrity and function. Autophagy is regulated by multiple pathways that are either dependent or independent of mTOR (mechanistic target of rapamycin; a.k.a. mammalian target of rapamycin), a master regulatory molecules that impacts several cellular functions. In this review, we summarize the role of autophagy in Mtb pathogenesis, the mTOR pathway and, modulating the mTOR pathway with inhibitors as potential adjunctive HDT, in combination with standard anti-TB antibiotics, to improve the outcome of current TB treatment.

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“…After negatively regulated by this pathway [19]. The FoxP3+Treg cells activation which will assist to set up a new target for the involvement of TB immunotherapy molecules as part of the immune-escape mechanism to provide a theoretical basis is inhibited by M.tuberculosis [20].…”

Section: Some Beneficial Events With Respect To Host Cell Reverted Bymentioning

confidence: 99%

Stage specific classification of DEGs via statistical profiling and network analysis reveals potential biomarker associated with various stages of TB

Alam

Imam

Ahmed

et al. 2018

Preprint

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Background: Tuberculosis (TB) is a deadly transmissible disease that can infect almost any body-part of the host but is mostly infect the lungs. It is one of the top 10 causes of death worldwide. In the 30 high TB burden countries, 87% of new TB cases occurred in 2016. Seven countries: India, Indonesia, China, Philippines, Pakistan, Nigeria, and South Africa accounted for 64% of the new TB cases. To stop the infection and progression of the disease, early detection of TB is important. In our study, we used microarray data set and compared the gene expression profiles obtained from blood samples of patients with different datasets of Healthy control, Latent infection, Active TB and performed network-based analysis of DEGs to identify potential biomarker. Objectives: We want to observe the transition of genes from normal condition to different stages of the TB and identify, annotate those genes/pathways/processes that play key role in the progression of TB disease during its cyclic interventions in human body. Results: We identified 319 genes that are differentially expressed in various stages of TB (Normal to LTTB, Normal to Active TB and LTTB to active TB) and allocated to pathways from multiple databases which comprised of curated class of associated genes. These pathway's importance was then evaluated according to the no. of DEGs present in the pathway and these genes show the broad spectrum of processes that take part in every state. In addition, we studied the regulatory networks of these classified genes, network analysis does consider the interactions between genes (specific for TB) or proteins provide us new facts about TB disease, which in turn can be used for potential biomarkers identification. We identified total 29 biomarkers from various comparison groups of TB stages in which 14 genes are over expressed as host responses against pathogen, but 15 genes are down regulated that means these genes has allowed the process of host defense to cease and give time to pathogen for its progression. Conclusions:This study revealed that gene-expression profiles can be used to identify and classified the genes on stage specific pattern among normal, LTTB and active TB and network modules associated with various stages of TB were elucidated, which in turn provided a basis for the identification of potential pathways and key regulatory genes that may be involved in progression of TB disease.association' presumption, that means the physically and functionally linked genes are possibly participated in the same biological-pathways having comparable effects on the phenotypes[3]. The concept of network theory is an imperative method to know the topological properties and the complex-systems dynamics correspond to their functional modules. The complex networks may be classified into four types of networks: (a) scale-free network, (b) small-world network, (c) random network and (d) hierarchical network. For the biologist,hierarchical network has special interest because it incorporates the mien of modules and distributed h...

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Inhibition of the PI3K-Akt-mTOR signaling pathway in T lymphocytes in patients with active tuberculosis

Abstract: The PI3K-Akt-mTOR signaling pathway in T lymphocytes and CD4CD25FoxP3T cells was inhibited, which could explain why M.tuberculosis can induce FoxP3T cell to expand.

Cited by 32 publications

References 20 publications

Epithelial Cells Attenuate Toll-Like Receptor-Mediated Inflammatory Responses in Monocyte-Derived Macrophage-Like Cells to Mycobacterium tuberculosis by Modulating the PI3K/Akt/mTOR Signaling Pathway

Epithelial Cells Attenuate Toll-Like Receptor-Mediated Inflammatory Responses in Monocyte-Derived Macrophage-Like Cells to Mycobacterium tuberculosis by Modulating the PI3K/Akt/mTOR Signaling Pathway

Harnessing the mTOR Pathway for Tuberculosis Treatment

Stage specific classification of DEGs via statistical profiling and network analysis reveals potential biomarker associated with various stages of TB

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