Immunometabolism In The Context Of Infection
Diet-mediated immunometabolic regulation promotes pathogen clearance
It is increasingly recognized that live bacterial pathogens exploit immunometabolism for their persistence. We hypothesize that altering the host metabolism may restore effective immune responses that clear the pathogens. While dietary interventions have been applied successfully in the treatment of various metabolic diseases, including cancer, through their effect on metabolism and the immune response, this approach has been overlooked in infectious diseases in favor of traditional pathogen-centric clearance methods. Notably, the effects of diet are not restricted to the gut mucosa but also include a systemic influence on immune cell function in extra-intestinal organs, including the lung. Using various mouse pneumonia models and the multidrug-resistant (MDR) bacteria, K. pneumoniae (Kp) and S. aureus (Sa), we explore the host metabolic pathways that facilitate immune suppression and disease tolerance, assessing whether they can be targeted by diet-based or pharmacological strategies for bacterial clearance. To elucidate the exact mechanisms underlying improved pathogen clearance from the lungs, we employ single-cell transcriptomics, flow cytometry, epigenetic assays, metabolomics, spatial metabolite imaging, and indirect calorimetry.
Role of peripheral metabolic pathways (tryptophan/kynurenine metabolism) during pneumonia
A major focus of our lab is understanding how peripheral metabolic pathways shape immune responses during pneumonia. We study the tryptophan–kynurenine pathway, in which the enzymes IDO1 and IDO2 initiate the conversion of tryptophan to kynurenine and subsequently nicotinamide adenine dinucleotide (NAD⁺, de novo synthesis), a key regulator of mitochondrial function and cellular metabolism. Using mouse models lacking IDO1, IDO2, or both enzymes, we investigate how this metabolic pathway influences airway immune responses and the ability of the host to clear bacterial infection.
Effect of immunometabolites on bacterial adaptation
Successful bacterial pathogens exhibit remarkable adaptability to microenvironmental changes. We investigate how accumulated mitochondrial metabolites such as itaconate and fumarate directly influence bacterial adaptation, driving the selection of variants optimized for survival in the challenging metabolic milieu generated by activated immune and stromal cells. Our research specifically focuses on the Type VI Secretion System (T6SS) in Klebsiella pneumoniae and the enzyme FumC in Staphylococcus aureus.
