Airway immunometabolites fuel Pseudomonas aeruginosa infection
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REVIEW
Airway immunometabolites fuel Pseudomonas aeruginosa infection Sebastián A. Riquelme and Alice Prince*
Abstract Pulmonary infections are associated with a brisk inflammatory reaction to bacterial surface components. Lipopolysaccharides (LPS) trigger macrophage activation and release of mitochondrial metabolites that control the intensity of the immune response. Whereas succinate induces oxidative stress (ROS), HIF1α stabilization, glycolysis and IL-1β release, itaconate suppresses inflammation by inhibiting succinate oxidation, glycolytic flux and promoting antioxidant Nrf2-HO-1 functions. P. aeruginosa is a major pathogen associated with acute and chronic lung infection. Although both secreted toxins, LPS and proteases are key factors to establish acute P. aeruginosa pneumonia, lack of these components in chronic P. aeruginosa isolates suggest these organisms exploit other mechanisms to adapt and persist in the lung. Upon inhalation, P. aeruginosa strains trigger airway macrophage reprograming and bacterial variants obtained from acutely and chronically infected subjects exhibit metabolic adaptation consistent with succinate and itaconate assimilation; namely, high expression of extracellular polysaccharides (EPS), reduced lptD-LPS function, increased glyoxylate shunt (GS) activity and substantial biofilm production. In this review we discuss recent findings illustrating how P. aeruginosa induces and adapts to macrophage metabolites in the human lung, and that catabolism of succinate and itaconate contribute to their formidable abilities to tolerate oxidative stress, phagocytosis and immune clearance. Keywords: Pseudomonas aeruginosa, Pneumonia, Succinate, Itaconate, Immunometabolism, Biofilm, Adaptation, Cystic fibrosis, ROS, Metabolic stress Background Opportunistic bacterial pathogens, such as Pseudomonas aeruginosa, Klebsiella pneumoniae and Staphylococcus aureus are frequently associated with persistent pulmonary infection [1, 2]. These pathogens are a major cause of morbidity and mortality, especially in individuals with damaged airways, as occurs in ventilator associated pneumonia (VAP) [3–6], in subjects with antecedent viral infection [7–10], or in patients exhibiting airway inflammation, as in chronic obstructive pulmonary disease (COPD) [11, 12] and in cystic fibrosis (CF) [13– 16]. Antibiotic resistance is a common feature of these organisms, and may contribute to intractable infection, but even susceptible strains are able to cause chronic *Correspondence: [email protected] Department of Pediatrics, Columbia University, New York, NY 10032, USA
inflammation and eventual mortality, suggesting mechanisms other than drug resistance are involved in pulmonary pathogenesis. It is also curious that ex vivo, many of these bacteria are readily phagocytosed and killed by immune cells, suggesting that conditions within the airway itself, such as the complex metabolic milieu provided by inflammatory cells, may contribute to bacterial survival [1, 2]. The ability of these major opportunists t
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