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

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:10.1038/s41467-020-19095-z

Cited by 48 publications

(44 citation statements)

References 73 publications

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“…A beneficial effect of metformin on in vivo Mtb clearance was also shown by Bohme et al In Mtb-infected mice that received metformin along with pyrazinamide and isoniazid for 30 days, bacterial burden was compared to mice having received only pyrazinamide and isoniazid [83] confirming that metformin can enhance the sterilizing activity of available antimicrobial treatment for Mtb infection. Conducting subsequent mechanistic experiments, the authors revealed that metformin enhances the host immune function against Mtb via reprograming CD8(+) T cell metabolism, favoring in the expansion of memory CD8+CXCR3+ T cells population with anti-Mtb properties.…”

Section: Metforminsupporting

confidence: 59%

Diabetes-associated Susceptibility to Tuberculosis: Contribution of Hyperglycemia vs. Dyslipidemia

Ngo

Bartlett

Ronacher

2021

Preprint

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Diabetes is a major risk factor for tuberculosis (TB). Diabetes increases the risk of progression from latent tuberculosis infection (LTBI) to active pulmonary TB and TB patients with diabetes are at greater risk of more severe disease and adverse TB treatment outcomes compared to TB patients without co-morbidities. Diabetes is a complex disease characterized not only by hyperglycemia but also various forms of dyslipidemia. However, the relative contribution of these underlying metabolic factors to increased susceptibility to TB are poorly understood. This review summarizes our current knowledge on epidemiology and clinical manifestation of TB and diabetes comorbidity. We subsequently dissect the relative contribution of body mass index, hyperglycemia, elevated cholesterol and triglycerides on TB disease severity and treatment outcomes. Lastly, we discuss the impact of selected glucose and cholesterol lowering treatments frequently used in the management of diabetes on TB treatment outcomes.

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Section: Metforminsupporting

confidence: 59%

Diabetes-associated Susceptibility to Tuberculosis: Contribution of Hyperglycemia vs. Dyslipidemia

Ngo

Bartlett

Ronacher

2021

Preprint

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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 ultimately drive antigen-induced immune function(46, 47, 50). These data suggest that attempts to modulate metabolic and immune mechanisms should be applied in an endotype-specific manner.…”

Section: Discussionmentioning

confidence: 99%

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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“…It is also demonstrated that prolonging boosting intervals can induce a stronger booster response and enhanced long-term protective efficacy against M. tuberculosis [ 28 , 33 ]. Metformin could expand memory-like antigen-inexperienced CD8 + T cells and enhance protective efficacy against M. tuberculosis challenge [ 34 ]. Some studies have demonstrated that IL-7 and IL-15 can promote formation and homeostasis of memory T cells [ 35 , 36 ].…”

Section: Discussionmentioning

confidence: 99%

Fusion Cytokines IL-7-Linker-IL-15 Promote Mycobacterium Tuberculosis Subunit Vaccine to Induce Central Memory like T Cell-Mediated Immunity

Bai

Zhou

et al. 2020

Vaccines

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Tuberculosis (TB), caused by Mycobacterium tuberculosis (M. tuberculosis), is among the most serious infectious diseases worldwide. Adjuvanted protein subunit vaccines have been demonstrated as a kind of promising novel vaccine. This study proposed to investigate whether cytokines interliukine-7 (IL-7) and interliukine-15 (IL-15) help TB subunit vaccines induce long-term cell-mediated immune responses, which are required for vaccination against TB. In this study, mice were immunized with the M. tuberculosis protein subunit vaccines combined with adnovirus-mediated cytokines IL-7, IL-15, IL-7-IL-15, and IL-7-Linker-IL-15 at 0, 2, and 4 weeks, respectively. Twenty weeks after the last immunization, the long-term immune responses, especially the central memory-like T cells (TCM like cell)-mediated immune responses, were determined with the methods of cultured IFN-γ-ELISPOT, expanded secondary immune responses, cell proliferation, and protective efficacy against Mycobacterium bovis Bacilli Calmette-Guerin (BCG) challenge, etc. The results showed that the group of vaccine + rAd-IL-7-Linker-IL-15 induced a stronger long-term antigen-specific TCM like cells-mediated immune responses and had higher protective efficacy against BCG challenge than the vaccine + rAd-vector control group, the vaccine + rAd-IL-7 and the vaccine + rAd-IL-15 groups. This study indicated that rAd-IL-7-Linker-IL-15 improved the TB subunit vaccine’s efficacy by augmenting TCM like cells and provided long-term protective efficacy against Mycobacteria.

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

Cited by 48 publications

References 73 publications

Diabetes-associated Susceptibility to Tuberculosis: Contribution of Hyperglycemia vs. Dyslipidemia

Diabetes-associated Susceptibility to Tuberculosis: Contribution of Hyperglycemia vs. Dyslipidemia

Gene expression signatures identify biologically and clinically distinct tuberculosis endotypes

Fusion Cytokines IL-7-Linker-IL-15 Promote Mycobacterium Tuberculosis Subunit Vaccine to Induce Central Memory like T Cell-Mediated Immunity

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