IDO-dependent metabolic reprogramming promotes K. pneumoniae airway infection 2255572

Introduction Klebsiella pneumoniae (Kp) is a leading cause of pneumonia-associated morbidity and mortality in healthcare settings. One strategy by which Kp evades immune clearance is through its modulation of host metabolic pathways. We hypothesize that Kp exploits the host tryptophan catabolic pathway, initiated by the enzymes indoleamine 2,3-dioxygenase 1 and 2 (Ido1/2), to produce immunosuppressive molecules known collectively as kynurenines, thereby impairing effective immune clearance in the airway Methods Using a murine pneumonia model in wild-type BL/6 and Ido1/2⁻/⁻ mice, we compared bacterial burden and altered immune landscape. We also investigated the metabolic response within lung tissues by spatial metabolite imaging (DESI-mass spectrometry). Results We showed that the Ido1/2⁻/⁻ animals exhibited improved survival, lower airway bacterial burden, and enhanced recruitment of neutrophils and T cells. Neutrophil depletion worsened the infection, particularly in the Ido1/2⁻/⁻ mice, suggesting a key role for Ido1/2 in suppressing an effective neutrophil recruitment and response at the site of infection. Notably, lungs from the infected Ido1/2⁻/⁻ mice showed elevated levels of AMP, a metabolite indicative of AMP-activated protein kinase (AMPK) activity. These findings suggest that Ido1/2 may limit neutrophilic immunity at least in part through the suppression of AMPK signaling. Conclusion Targeting tryptophan metabolism or AMPK may thus represent a promising host-directed approach to enhance immunity against recalcitrant multidrug-resistant bacterial infections. Funding Source NIH K99/R00 HL157550 (NHLBI); NIH R35 GM160393 (NIGMS)