Immunometabolic Regulation of Bacterial Infection, Biofilms, and Antibiotic Susceptibility.

BACKGROUND: Upon infection, mucosal tissues activate a brisk inflammatory response to clear the pathogen, i.e., resistance to disease. Resistance to disease is orchestrated by tissue-resident macrophages, which undergo profound metabolic reprogramming after sensing the pathogen. These metabolically activated macrophages release many inflammatory factors, which promote their bactericidal function. However, in immunocompetent individuals, pathogens like Pseudomonas aeruginosa, Staphylococcus aureus, and Salmonella evade this type of immunity, generating communities that thrive for the long term. SUMMARY: These organisms develop features that render them less susceptible to eradication, such as biofilms and increased tolerance to antibiotics. Furthermore, after antibiotic therapy withdrawal, "persister" cells rapidly upsurge, triggering inflammatory relapses that worsen host health. How these pathogens persisted in inflamed tissues replete with activated macrophages remains poorly understood. KEY MESSAGES: In this review, we discuss recent findings indicating that the ability of P. aeruginosa, S. aureus, and Salmonella to evolve biofilms and antibiotic tolerance is promoted by the similar metabolic routes that regulate macrophage metabolic reprogramming.

Ketogenesis promotes tolerance to Pseudomonas aeruginosa pulmonary infection.

Pseudomonas aeruginosa is a common cause of pulmonary infection. As a Gram-negative pathogen, it can initiate a brisk and highly destructive inflammatory response; however, most hosts become tolerant to the bacterial burden, developing chronic infection. Using a murine model of pneumonia, we demonstrate that this shift from inflammation to disease tolerance is promoted by ketogenesis. In response to pulmonary infection, ketone bodies are generated in the liver and circulate to the lungs where they impose selection for P. aeruginosa strains unable to display surface lipopolysaccharide (LPS). Such keto-adapted LPS strains fail to activate glycolysis and tissue-damaging cytokines and, instead, facilitate mitochondrial catabolism of fats and oxidative phosphorylation (OXPHOS), which maintains airway homeostasis. Within the lung, P. aeruginosa exploits the host immunometabolite itaconate to further stimulate ketogenesis. This environment enables host-P. aeruginosa coexistence, supporting both pathoadaptive changes in the bacteria and the maintenance of respiratory integrity via OXPHOS.