The Crosstalk Between Microbial-Derived Extracellular Vesicles and Host Immune Checkpoints: A Molecular Perspective on Chronic Inflammation and Immune Evasion
Abstract
Bacterial extracellular vesicles (EVs) are increasingly recognized as major regulators at the dynamic host-microbiota interface. Nanosized vesicles that were originally considered as cellular debris are now appreciated for their powerful regulatory function and the variety of bioactive molecules (proteins, nucleic acids, lipids, and metabolites) that modulate immune responses included within them. In this review, we dissect the complex interplay between microbial EVs and immune checkpoint players, such as PD-1/PD-L1, CTLA-4, TIM-3, and LAG-3, which are crucial to preserve immune tolerance but can be hijacked during chronic inflammation, infection, or cancer.
This review introduces the biology and biogenesis of microbial EVs and the architecture and specific function of canonical immune checkpoints. It also explores how microbial EVs may upregulate checkpoint ligands, increase regulatory T cells, suppress cytotoxicity, and modulate dendritic cell function, underscoring their dual function in immune suppression and homeostasis. In chronic infectious diseases such as tuberculosis and H. pylori or immunological-based diseases such as IBD and cancer, microbial EVs are instrumental in immune evasion and in disease development.
From a therapeutic standpoint, microbial EVs constitute another exciting frontier: they can be engineered for immune modulation, small molecule delivery or vaccine formulations. Furthermore, the detection of these in biofluids, make them potential diagnostic as non-invasive biomarkers of immune dysregulation. Although there have been exciting progresses, barriers remain in the standardization of EV isolation, as well as in larger definition of the context-dependent effects. Ultimately, characterisation of EV–immune checkpoint axis might revolutionise strategies for treatment of chronic inflammation, chronic infections and immune mediated diseases.
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Copyright (c) 2025 Shahad K.Al-Qaisi Al-Qaisi, Raya K. ibrahem Ibrahem, Suha Khaleel Ibrahim Ibrahim
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