Berberine promotes host lipolysis to enhance antimicrobial defense against hypervirulent Klebsiella pneumoniae infection

초록

Hypervirulent Klebsiella pneumoniae (hvKp) is an emerging pathogen that causes severecommunity-acquired infections; however, the immune mechanisms controlling intracellularhvKp have yet to be clearly defined. In this study, we investigated the therapeutic potentialof berberine against hvKp infection and elucidated the underlying molecular mechanismsusing macrophage cell models and in vivo zebrafish models. Berberine significantly reducedintracellular hvKp survival in macrophages and improved survival in hvKp-infected zebrafish. Berberine markedly attenuated proinflammatory cytokine production and inhibited thec-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) signaling pathways. Notably, we found that hvKp exploited host lipid droplets (LD) biosynthesis to supportits intracellular survival, and berberine effectively suppressed LD accumulation. Mechanistically,berberine promoted the nuclear translocation of transcription factor EB (TFEB), therebyenhancing lipolysis. Although berberine upregulated autophagy-related gene expressionduring hvKp infection, it did not induce lipophagy, the selective autophagic degradation ofLD. Collectively, these findings indicate that berberine has potential as a therapeutic agentagainst hvKp infection by modulating host lipid metabolism to restrict bacterial intracellularsurvival.

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