Epidermal Growth Factor Receptor-responsive indoleamine 2, 3 dioxygenase confers immune homeostasis during S. flexneri infection.

The resolution of S. flexneri infection-associated hyperinflammation is crucial for host survival. Using in vitro and in vivo models of Shigellosis, we find that S. flexneri induces the expression of indoleamine 2, 3 dioxygenase 1 (IDO1) through NOD2 and Epidermal Growth Factor Receptor (EGFR) signaling pathway. Congruently, abrogation of NOD2 or EGFR compromises the ability of S. flexneri to induce IDO1 expression. We observed that the loss of IDO1 function in vivo exacerbates Shigellosis by skewing inflammatory cytokine response, disrupting colon epithelial barrier integrity and consequently limiting host life span. Interestingly, administration of recombinant EGF rescued mice from IDO1 inhibition-driven aggravated Shigellosis by restoring the cytokine balance and subsequently restricting bacterial growth. This is the first study that underscores the direct implication of NOD2-EGFR axis in IDO1 production and its crucial homeostatic contributions during Shigellosis. Together, this study unravels EGF as a potential therapeutic intervention for infectious diseases.