Metabolic reprogramming of immune cells in the battle against intracellular bacterial chronic infections: novel mechanisms and breakthroughs.

Chronic intracellular bacterial infections persist within host cells by evading immune clearance, imposing prolonged metabolic stress on the host. In response, the immune system undergoes metabolic reprogramming to sustain prolonged defense. A key feature of this reprogramming is the shift from oxidative phosphorylation (OXPHOS) to aerobic glycolysis, which enhances pro-inflammatory and antimicrobial responses. Concurrently, fatty acid and amino acid catabolism provide additional metabolic support. Beyond shaping immune function, these metabolic shifts also influence the trajectory of infection by altering the host-pathogen metabolic interplay. In this review, we focus primarily on Mycobacterium tuberculosis (Mtb) infection and integrate quantitative flux analyses of carbon and nitrogen distribution, emphasizing how these metabolic changes connect to epigenetic regulation. We also explore metabolic reprogramming in five representative immune cell types-comprising both innate and adaptive immune cells-to elucidate how their distinct metabolic profiles influence host defense mechanisms and disease progression. Building on these foundations, we propose an innovative metabolic competition model between host and pathogen, offering new insights into the intricate interplay of metabolic networks in chronic intracellular infections.