Ribosome-Targeting Antibiotics Impair T Cell Effector Function and Ameliorate Autoimmunity by Blocking Mitochondrial Protein Synthesis

Almeida, Luís; Dhillon-LaBrooy, Ayesha; Castro, Carla; Adossa, Nigatu; Carriche, Guilhermina M.; Guderian, Melanie; Lippens, Saskia; Dennerlein, Sven; Hesse, Christina; Lambrecht, Bart N.; Berod, Luciana; Schauser, Leif; Blazar, Bruce R.; Kalesse, Markus; Müller, Rolf; Moita, Luís F.; Sparwasser, Tim

doi:10.1016/j.immuni.2020.11.001

Cited by 61 publications

(54 citation statements)

References 82 publications

(93 reference statements)

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“…The relationship between mitochondrial translation and increased mitochondrial activity is not unique to 39°C T E cells and it is well documented that upon activation, T cells undergo mitochondrial biogenesis and require mitochondrial translation for correct polarization or function (10,13,17,20,21,25). However, in experiments that targeted mitochondrial translation, it was evident that 39°C T E cells were more sensitive to mitochondrial translation impairment than 37°C T E cells.…”

Section: Discussionmentioning

confidence: 99%

Fever supports CD8 ⁺ effector T cell responses by promoting mitochondrial translation

O’Sullivan

Stanczak

Villa

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Fever can provide a survival advantage during infection. Metabolic processes are sensitive to environmental conditions, but the effect of fever on T cell metabolism is not well characterized. We show that in activated CD8+ T cells, exposure to febrile temperature (39 °C) augmented metabolic activity and T cell effector functions, despite having a limited effect on proliferation or activation marker expression. Transcriptional profiling revealed an up-regulation of mitochondrial pathways, which was consistent with increased mass and metabolism observed in T cells exposed to 39 °C. Through in vitro and in vivo models, we determined that mitochondrial translation is integral to the enhanced metabolic activity and function of CD8+ T cells exposed to febrile temperature. Transiently exposing donor lymphocytes to 39 °C prior to infusion in a myeloid leukemia mouse model conferred enhanced therapeutic efficacy, raising the possibility that exposure of T cells to febrile temperatures could have clinical potential.

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Section: Discussionmentioning

confidence: 99%

Fever supports CD8 ⁺ effector T cell responses by promoting mitochondrial translation

O’Sullivan

Stanczak

Villa

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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“…In an obesity-associated liver cancer model, LTA in the liver enhanced the senescence-associated secretory phenotype of hepatic stellate cells (HSCs) and upregulated COX2 expression and prostaglandin E 2 (PGE 2 ) production in the senescent HSCs, which in turn suppressed antitumor immune response through the PGE 2 receptor on immune cells (35). It's worth to mention that some antibiotics can elicit immune cell response, independent of microbiota dysbiosis, by inhibiting the respiratory activity (36), or blocking the mitochondrial protein synthesis in immune cells (37). The antibiotics cocktail in this study was widely used to investigate the role of the gut microbiota in modulation of host immune response, and the side effects were rarely considered (5,6,(8)(9)(10).…”

Section: Discussionmentioning

confidence: 99%

Depletion of Gut Microbiota Impairs Gut Barrier Function and Antiviral Immune Defense in the Liver

Guo

Zhou

et al. 2021

Front. Immunol.

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Commensal gut microbiota protects the immune defense of extra-intestinal organs. Gut microbiota depletion by antibiotics can impair host antiviral immune responses and alter hepatitis B virus (HBV) infection outcomes. However, how gut microbiota modulates antiviral immune response in the liver remains unclear. Here, mice were treated with broad-spectrum antibiotics to deplete gut microbiota. Gut integrity was evaluated, and translocation of live commensal gut bacteria and their components into the liver was investigated. An HBV infection model was established to evaluate impairment of antiviral immune response in the liver after gut microbiota depletion. We found that gut microbiota depletion was associated with impairment of colon epithelial integrity, and live commensal gut microbiota could translocate to the liver. Further, T cell antiviral function in the liver was impaired, partially relying on enhanced PD-1 expression, and HBV immune clearance was hampered. In conclusion, gut microbiota depletion by antibiotics can impair gut barrier function and suppress T cell antiviral immune response in the liver.

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“…As the mechanistic target of macrolide antibiotics is the S50-subunit of bacterial ribosomes [ 14 ], and mitochondria are believed to be of bacterial origin [ 21 ], we hypothesized that inhibition of mitochondrial translation could be an effect of macrolide treatment. Recently, metabolic modulation has been shown to influence T cell fate decisions, and the antibiotic linezolid inhibits Th17 cell formation by interfering with mitochondrial translation [ 22 ]. However, when we checked for expression of the exclusively mitochondrial translated cytochrome c oxidase, no difference between treated and untreated cultures could be detected (Fig.…”

Section: Resultsmentioning

confidence: 99%

Clarithromycin impairs tissue-resident memory and Th17 responses to macrolide-resistant Streptococcus pneumoniae infections

et al. 2021

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The increasing prevalence of antimicrobial resistance in pathogens is a growing public health concern, with the potential to compromise the success of infectious disease treatments in the future. Particularly, the number of infections by macrolide antibiotics-resistant Streptococcus pneumoniae is increasing. We show here that Clarithromycin impairs both the frequencies and number of interleukin (IL)-17 producing T helper (Th) 17 cells within the lungs of mice infected with a macrolide-resistant S. pneumoniae serotype 15A strain. Subsequently, the tissue-resident memory CD4+ T cell (Trm) response to a consecutive S. pneumoniae infection was impaired. The number of lung resident IL-17+ CD69+ Trm was diminished upon Clarithromycin treatment during reinfection. Mechanistically, Clarithromycin attenuated phosphorylation of the p90-S6-kinase as part of the ERK pathway in Th17 cells. Moreover, a strong increase in the mitochondrial-mediated maximal respiratory capacity was observed, while mitochondrial protein translation and mTOR sisgnaling were unimpaired. Therefore, treatment with macrolide antibiotics may favor the spread of antimicrobial-resistant pathogens not only by applying a selection pressure but also by decreasing the natural T cell immune response. Clinical administration of macrolide antibiotics as standard therapy procedure during initial hospitalization should be reconsidered accordingly and possibly be withheld until microbial resistance is determined. Key messages • Macrolide-resistant S. pneumoniae infection undergoes immunomodulation by Clarithromycin • Clarithromycin treatment hinders Th17 and tissue-resident memory responses • Macrolide antibiotics impair Th17 differentiation in vitro by ERK-pathway inhibition

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Ribosome-Targeting Antibiotics Impair T Cell Effector Function and Ameliorate Autoimmunity by Blocking Mitochondrial Protein Synthesis

Cited by 61 publications

References 82 publications

Fever supports CD8 ⁺ effector T cell responses by promoting mitochondrial translation

Fever supports CD8 ⁺ effector T cell responses by promoting mitochondrial translation

Depletion of Gut Microbiota Impairs Gut Barrier Function and Antiviral Immune Defense in the Liver

Clarithromycin impairs tissue-resident memory and Th17 responses to macrolide-resistant Streptococcus pneumoniae infections

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Ribosome-Targeting Antibiotics Impair T Cell Effector Function and Ameliorate Autoimmunity by Blocking Mitochondrial Protein Synthesis

Cited by 61 publications

References 82 publications

Fever supports CD8 + effector T cell responses by promoting mitochondrial translation

Fever supports CD8 + effector T cell responses by promoting mitochondrial translation

Depletion of Gut Microbiota Impairs Gut Barrier Function and Antiviral Immune Defense in the Liver

Clarithromycin impairs tissue-resident memory and Th17 responses to macrolide-resistant Streptococcus pneumoniae infections

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Fever supports CD8 ⁺ effector T cell responses by promoting mitochondrial translation

Fever supports CD8 ⁺ effector T cell responses by promoting mitochondrial translation