Bartonella henselae Subverts Host Cell Apoptosis by Linking Intracellular NOD2 Sensing to an AREG/EGFR Autocrine Survival Loop

Bartonella henselae establishes persistent infections by manipulating host cell survival, but mechanisms beyond the known Type IV Secretion System (T4SS)-cAMP pathway are poorly understood. Here, we delineate a novel anti-apoptotic axis in human endothelial cells hijacked by B. henselae. We found infection upregulates the pro-survival factor Amphiregulin (AREG). This induction is initiated by the intracellular sensor NOD2, which triggers a PI3K/AKT/CREB signaling cascade, culminating in CREB-dependent transcription of AREG. Functional studies confirmed that secreted AREG acts via its receptor, EGFR, to suppress apoptosis, establishing a complete NOD2-AREG-EGFR autocrine loop. Collectively, our findings characterize a sophisticated survival strategy where B. henselae links intracellular innate immune sensing to the activation of an autocrine growth factor loop. The delineation of this novel NOD2-AREG-EGFR axis reveals a parallel mechanism of host cell manipulation, adding a new layer of complexity to our understanding of Bartonella-host interactions.