Autophagy induced by taurolidine protects against polymicrobial sepsis by promoting both host resistance and disease tolerance.

SignificanceDisease resistance and tolerance are evolutionarily conserved yet distinct defense strategies that protect the host against microbial infection. Here, we report that taurolidine administered before the start of infection confers protection against polymicrobial sepsis by promoting resistance and tolerance. Notably, taurolidine given after the onset of infection also rescues mice from sepsis-associated lethality by enhancing disease tolerance to organ damage. This protection relies on an intact autophagy pathway, as taurolidine fails to protect autophagy-deficient mice against microbial sepsis. Specifically, taurolidine induces light chain 3-associated phagocytosis, but not xenophagy, in macrophages, resulting in an augmented bactericidal activity with enhanced cellular resistance to infection. These results highlight the importance of autophagy induction for taurolidine-augmented host resistance and disease tolerance and subsequent protection.