Mechanisms and strategies of host xenophagy manipulation by intracellular bacteria

Xenophagy, a specialized form of autophagy, serves as a critical cellular defense mechanism, targeting and degrading intracellular bacterial pathogens. This review explores the intricate interplay between bacteria and host xenophagy, focusing on the mechanisms that underlie xenophagic recognition, encapsulation, and degradation of bacterial invaders. Despite xenophagy's essential role in host immunity, many bacteria have evolved sophisticated strategies to evade, inhibit, or even subvert this process, ensuring their survival within host cells. We provide an in-depth analysis of the bacterial mechanisms that counteract xenophagy, detailing how specific pathogens manipulate autophagosome formation, acidification, and autophagosome-lysosome fusion. Furthermore, we highlight outstanding research questions, including the mechanisms of autophagosome formation at the bacterial surface, the interaction between xenophagy and the immune system, and the impact of xenophagy on bacterial antibiotic resistance. By examining the evolving understanding of xenophagy and bacterial countermeasures, this review underscores the potential for therapeutic strategies targeting xenophagy to enhance host defense against persistent intracellular bacterial infections.