Bacteria-induced immunological tolerance requires metabolic reprogramming of infected macrophages 9215

Abstract Description The architectural framework of mammalian lungs provides maximal gas exchange to replenish oxygen supply but poses a potential risk of exposure to various airborne pathogens. A healthy human lung effectively mitigates the basal microbial threat and can maintain a pathogen-free state despite filtering non-sterile air. This is due to the remarkable capacity of alveolar macrophages of the lung to eliminate any inhaled bacteria and restore a homeostatic state. However, bacterial exposure likely impacts the alveolar macrophage reactivity to a subsequent bacterial challenge by an immunological mechanism referred to as innate memory. In this study, we investigated whether macrophages infected with different bacteria trigger an altered response when subsequently given a second bacterial challenge. We discovered that primary bacterial exposure induced an immunological tolerance, resulting in lower secretion of pro-inflammatory cytokines and chemokines upon reinfection. Additionally, prior exposure to bacteria resulted in reduced phagocytosis and increased persistence upon a subsequent bacterial challenge. Exploring the mechanistic basis of this tolerance, we established a critical role of metabolic reprogramming of infected cells in inducing tolerogenic training. Notably, glycolysis and tricarboxylic acid cycle inhibition significantly restored normal macrophage functioning. The findings could have profound negative implications for patients with recurrent bacterial infections. Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)