The final gate: bacterial subversion of autophagosome-lysosome fusion as a conserved immune evasion strategy.

Abstract

Autophagy is a vital component of the host cell intracellular defense arsenal, culminating in the fusion of autophagosomes with lysosomes to degrade invading pathogens. While autophagosome formation has been extensively studied, recent insights reveal that the final fusion step constitutes a critical immunological bottleneck that is highly vulnerable to microbial sabotage. In this review, we synthesize evidence from diverse pathogens, including Mycobacterium tuberculosis, Salmonella enterica, Treponema pallidum, Helicobacter pylori, Coxiella burnetii, Yersinia pestis, and Porphyromonas gingivalis, demonstrating that autophagosome-lysosome fusion blockade is not incidental but represents a convergently evolved immune evasion strategy. We dissect three mechanistic strategies employed by these pathogens: disruption of RAB GTPases, interference with the HOPS and SNARE complexes, and inhibition or misregulation of lysosomal biogenesis and positioning. Each strategy targets the fusion machinery with remarkable specificity, often hijacking host regulatory circuits. We further discuss how these insights inform therapeutic interventions aimed at restoring autophagic flux. Fusion arrest emerges as a unifying hallmark of pathogen survival, positioning autophagosome-lysosome fusion as a critical frontier in the host-pathogen conflict. We advocate a paradigm shift from studying autophagy initiation markers to evaluating fusion competence as a functional measure of autophagic immunity.