Fatty acid metabolism in neutrophils promotes lung damage and bacterial replication during tuberculosis

Mycobacterium tuberculosis (Mtb) infection induces a marked influx of neutrophils into the lungs, which intensifies the severity of tuberculosis (TB). The metabolic state of neutrophils significantly influences their functional response during inflammation and interaction with bacterial pathogens. However, the effect of Mtb infection on neutrophil metabolism and its consequent role in TB pathogenesis remain unclear. In this study, we examined the contribution of glycolysis and fatty acid metabolism on neutrophil responses to Mtb HN878 infection using ex-vivo assays and murine infection models. We discover that blocking glycolysis aggravates TB pathology, whereas inhibiting fatty acid oxidation (FAO) yields protective outcomes, including reduced weight loss, immunopathology, and bacterial burden in lung. Intriguingly, FAO inhibition preferentially disrupts the recruitment of a pathogen-permissive immature neutrophil population (Ly6Glo/dim), known to accumulate during TB. Targeting carnitine palmitoyl transferase 1a (Cpt1a)-a crucial enzyme in mitochondrial beta-oxidation-either through chemical or genetic methods impairs neutrophils' ability to migrate to infection sites while also enhancing their antimicrobial function. Our findings illuminate the critical influence of neutrophil immunometabolism in TB pathogenesis, suggesting that manipulating fatty acid metabolism presents a novel avenue for host-directed TB therapies by modulating neutrophil functions. Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) is a significant global health issue. Neutrophils, immune cells that rapidly enter the lungs during Mtb infection, contribute both to fighting the infection and exacerbating lung damage. Their metabolic state, especially the way they produce energy, is crucial for their function during TB. However, the specific impact of Mtb on neutrophil metabolism and its role in TB progression has been unclear. In this study, we investigated the roles of glycolysis and fatty acid metabolism in neutrophil responses to Mtb infection. We found that inhibiting glycolysis worsens TB outcomes, while blocking fatty acid oxidation (FAO) provides protection, reducing lung damage, bacterial load, and overall disease severity. Notably, FAO inhibition specifically disrupts the accumulation of an immature neutrophil population that is more susceptible to Mtb, thereby improving infection control. Targeting carnitine palmitoyl transferase 1a (Cpt1a), a key enzyme in fatty acid metabolism, impaired neutrophil migration to infection sites and enhanced their antimicrobial activity. These findings suggest that modulating neutrophil metabolism, particularly through FAO inhibition, could be a promising strategy for developing host-directed TB therapies.