T cell toxicity induced by tigecycline binding to the mitochondrial ribosome

Area of Science:

• Immunology
• Molecular Biology
• Pharmacology

Background:

• Tetracyclines are protein synthesis inhibitors used to combat bacterial infections.
• Mitoribosomes, responsible for oxidative phosphorylation (OXPHOS), share similarities with bacterial ribosomes and may be targeted by these antibiotics.
• T cell activation and function rely on OXPHOS.

Purpose of the Study:

• To investigate the impact of ribosome-targeting antibiotics, specifically tigecycline, on human T cells.
• To elucidate the molecular mechanisms underlying tigecycline's cytotoxicity in T cells.

Main Methods:

• In vitro assessment of tigecycline's effects on T cell viability, proliferation, and activation.
• Measurement of mitochondrial and cytosolic translation inhibition.
• Analysis of mitochondrial respiratory chain complex expression.
• Cryo-electron microscopy (cryo-EM) to determine tigecycline binding sites on T cell mitoribosomes.

Main Results:

• Tigecycline demonstrated significant cytotoxicity towards human T cells.
• Inhibition of mitochondrial translation and expression of mitochondrial respiratory chain complexes I, III, and IV was observed.
• T cell activation and expansion were curtailed.
• Cryo-EM revealed tigecycline binding to three distinct sites on T cell mitoribosomes, including the peptidyl transferase center.

Conclusions:

• Tigecycline targets human mitoribosomes, leading to T cell dysfunction and cytotoxicity.
• The binding sites identified provide a structural basis for tigecycline's off-target effects in human cells.
• Findings offer insights into the anti-inflammatory properties of tetracyclines and inform future antibiotic design to minimize side effects.