Host autophagy in Staphylococcus aureus infection: Mechanisms of clearance, evasion, and therapeutic intervention.

Staphylococcus aureus is a facultative intracellular pathogen that persists within both professional and non-professional phagocytes, contributing to chronic and antibiotic-resistant infections. Autophagy, particularly xenophagy, serves as a central cell-autonomous defense pathway that can capture intracellular S. aureus and deliver it to lysosomes for degradation. However, the bacterium has evolved multiple strategies to subvert xenophagic clearance, including manipulation of bacteria-containing autophagosome maturation, blockade of autophagosome and lysosome fusion, and co-option of autophagy-related machinery to create intracellular survival niches. Recent studies have also identified host pathways that shape infection outcomes, including reprogramming of cell death cascades to simultaneously sustain host viability and suppress xenophagy, and co-option of mitophagy to eliminate bactericidal mitochondrial ROS. As illustrative examples, caspase-8 reprogramming uncouples host survival from effective xenophagy, and the HDAC11/IL10/mTOR/PINK1-PRKN axis drives mitophagy to suppress mitochondrial ROS. We further address the largely unexplored roles of chaperone-mediated autophagy and endosomal microautophagy in S. aureus infection, drawing on mechanistic paradigms from viral and mycobacterial infections. Since S. aureus can impair autophagosome maturation, lysosomal acidification, and fusion between bacteria-containing autophagosomes and lysosomes, enhancing autophagy initiation alone may not always translate into improved bacterial clearance. We therefore propose, as a testable hypothesis, that host-directed strategies aimed at restoring lysosomal competence, improving degradative flux, or neutralizing bacterial virulence mechanisms may complement or outperform upstream autophagy induction in selected infection contexts. However, this concept remains insufficiently validated, and direct comparative studies in relevant host cell types and animal models are needed before lysosome-directed approaches can be prioritized therapeutically.