A NOD2-Encoded Toggle Switch Resolves the Host–Microbe Battle Over Cyclic AMP Control

with therapeutic promise in colitis. eTOC Blurb: Pathogens hijack macrophages by inducing cAMP surges that help them evade clearance. Anandachar et al. identify a host "toggle switch" in which NOD2 and G proteins compete for GIV, driving a rapid and robust surge-to-plunge transition in cAMP. This temporal switch limits tolerogenic signaling, restores microbial clearance and barrier integrity, and unveils a targetable host pathway in infection and IBD. Highlights: Pathogens exploit cAMP surges in macrophages to block phagolysosomal killing of microbesGIV acts as a molecular "toggle" linking NOD2 sensing to Gαi-mediated cAMP controlStructural and mutagenesis studies reveal mutually exclusive binding of NOD2 and Gαi to GIVPharmacogenomic perturbations pinpoint PKA, not EPAC, as the critical downstream effectorOrganoid co-cultures show NOD2-GIV-PKA crosstalk safeguards microbial clearance and gut barrier integrity.