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 (Fig. 1 ). 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 (polyamine synthesis and tryptophan metabolism) during pneumonia
We postulate that metabolic pathways beyond those supporting core metabolism may favor tolerance to infection. During infection, Kp activates several peripheral metabolic pathways, including the urea cycle and arginine metabolism, whose biological significance remains understudied. These pathways correlate with the downstream production of polyamines in the lung of infected mice. We focus on the immunosuppressive role of polyamines and determine how peripheral routes involved in their generation control infection and modulate airway damage during pneumonia . In a similar vein, we are interested in the potential immune regulation exerted by kynurenine, the downstream product of tryptophan metabolism during pneumonia.
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.
