Metformin enhances anti-mycobacterial responses by educating immunometabolic circuits of CD8<sup>+</sup>T cells

Böhme, Julia; Martínez, Núria; Li, Shamin; Lee, Andrea; Marzuki, Mardiana; Tizazu, Anteneh Mehari; Ackart, David F.; Frenkel, Jessica Haugen; Todd, Alexandra; Lachmandas, Ekta; Lum, Josephine; Foo, Shihui; Ng, Tze Pin; Lee, Bernett; Larbi, Anis; Netea, Mihai G.; Basaraba, Randall J.; Crevel, Reinout van; Newell, Evan W.; Kornfeld, Hardy; Singhal, Amit

doi:10.1101/2020.08.26.269217

Cited by 3 publications

(2 citation statements)

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“…Many HDT candidates target these pathways. For example, metformin mediates the AKT-mTOR pathway, blunting cellular glycolysis and the TCA cycle leading to inhibition of chromatin conformational changes that drive antigen-induced immune function [29,32]. Another inhibitor of mTOR, everolimus decreased TB-induced lung damage [27].…”

Section: Discussionmentioning

confidence: 99%

Gene expression signatures identify biologically and clinically distinct tuberculosis endotypes

et al. 2022

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BackgroundIn vitro, animal model, and clinical evidence suggests that tuberculosis is not a monomorphic disease, and that host response to tuberculosis is protean with multiple distinct molecular pathways and pathologies (endotypes). We applied unbiased clustering to identify separate tuberculosis endotypes with classifiable gene expression patterns and clinical outcomes.MethodsA cohort comprised of microarray gene expression data from microbiologically confirmed tuberculosis patients were used to identify putative endotypes. One microarray cohort with longitudinal clinical outcomes was reserved for validation, as was two RNA-seq cohorts. Finally, a separate cohort of tuberculosis patients with functional immune responses was evaluated to clarify stimulated from unstimulated immune responses.ResultsA discovery cohort, including 435 tuberculosis patients and 533 asymptomatic controls, identified two tuberculosis endotypes. Endotype A is characterised by increased expression of genes related to inflammation and immunity and decreased metabolism and proliferation; in contrast, endotype B has increased activity of metabolism and proliferation pathways. An independent RNA-seq validation cohort, including 118 tuberculosis patients and 179 controls, validated the discovery results. Gene expression signatures for treatment failure were elevated in endotype A in the discovery cohort, and a separate validation cohort confirmed that endotype A patients had slower time to culture conversion, and a reduced cure rate. These observations suggest that endotypes reflect functional immunity, supported by the observation that tuberculosis patients with a hyperinflammatory endotype have less responsive cytokine production upon stimulation.ConclusionThese findings provide evidence that metabolic and immune profiling could inform optimisation of endotype-specific host-directed therapies for tuberculosis.

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Section: Discussionmentioning

confidence: 99%

Gene expression signatures identify biologically and clinically distinct tuberculosis endotypes

et al. 2022

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“…Correspondingly, metformin treatment has anti-mycobacterial benefits on cellular metabolism, immune function, and gene expression. In mice and T2DM patients, metformin-educated CD8 + T cells had increased oxidative phosphorylation, survival capacity and anti-mycobacterial properties ( 99 ). Correspondingly, metformin upregulates genes involved in ROS production and phagocytosis, while downregulating type 1 IFN response genes and inflammation (TNF-α, IL-1β, IL-6, IFN-γ, and IL-17) following Mtb stimulation ( 100 ).…”

Section: Effects Of T2dm On the Immunometabolic And Gene-transcriptio...mentioning

confidence: 99%

Immunologic, metabolic and genetic impact of diabetes on tuberculosis susceptibility

et al. 2023

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Due to the increasing prevalence of diabetes mellitus (DM) globally, the interaction between DM and major global diseases like tuberculosis (TB) is of great public health significance, with evidence of DM having about a three-fold risk for TB disease. TB defense may be impacted by diabetes-related effects on immunity, metabolism, and gene transcription. An update on the epidemiological aspects of DM and TB, and the recent trends in understanding the DM-associated immunologic, metabolic, and genetic mechanisms of susceptibility to TB will be discussed in this review. This review highlights gaps in the incomplete understanding of the mechanisms that may relate to TB susceptibility in type 2 DM (T2DM). Understanding these three main domains regarding mechanisms of TB susceptibility in T2DM patients can help us build practical treatment plans to lessen the combined burden of the diseases in rampant areas.

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Gene expression signatures identify biologically and clinically distinct tuberculosis endotypes

DiNardo

Rajapakshe

Gandhi

et al. 2020

Preprint

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Rationale: Host response is a critical factor determining susceptibility to tuberculosis (TB). A delicate balance should be maintained between intracellular immunity against Mycobacterium tuberculosis (Mtb) and minimizing detrimental immunopathology. Studies have identified incongruous immune responses that can lead to a similar TB disease phenotype. Instead of envisioning that susceptibility to TB follows a singular path, we propose the hypothesis that varied host endotypes exist within the TB clinical phenotype. Methods and Results: Unbiased clustering analysis from 12 publicly available gene expression datasets consisting of data from 717 TB patients and 527 controls, identified 4 TB patient endotypes with distinct immune responses. The two largest endotypes exhibit divergent metabolic, epigenetic and immune pathways. TB patient endotype A, comprising 333 TB patients (46.4%), is characterized by increased expression of genes important for i) glycolysis, ii) IL-2-STAT5, IL-6-STAT3, Type I and II Interferon IFN-γ and TNF signaling and iii) epigenetic-modifying genes. In contrast, TB patient endotype B, comprising 313 TB patients (43.6%), is characterized by i) upregulated NFAT and hormone metabolism, and ii) decreased glycolysis, IFN-γ and TNF signaling. In silico evaluation suggests therapies beneficial for endotype A could be detrimental to endotype B, and vice versa. Multiplex ELISA completed from an external validation cohort confirmed a TB patient sub-group with decreased immune upregulation. Conclusions: Host immunity to TB is heterogenous. Unbiased clustering analysis identified distinct TB endotypes with divergent metabolic, epigenetic and immune gene expression profiles that may enable stratified or personalized treatment management in the future.

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Metformin enhances anti-mycobacterial responses by educating immunometabolic circuits of CD8⁺T cells

Cited by 3 publications

References 71 publications

Gene expression signatures identify biologically and clinically distinct tuberculosis endotypes

Gene expression signatures identify biologically and clinically distinct tuberculosis endotypes

Immunologic, metabolic and genetic impact of diabetes on tuberculosis susceptibility

Gene expression signatures identify biologically and clinically distinct tuberculosis endotypes

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Metformin enhances anti-mycobacterial responses by educating immunometabolic circuits of CD8+T cells

Cited by 3 publications

References 71 publications

Gene expression signatures identify biologically and clinically distinct tuberculosis endotypes

Gene expression signatures identify biologically and clinically distinct tuberculosis endotypes

Immunologic, metabolic and genetic impact of diabetes on tuberculosis susceptibility

Gene expression signatures identify biologically and clinically distinct tuberculosis endotypes

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Metformin enhances anti-mycobacterial responses by educating immunometabolic circuits of CD8⁺T cells