Pseudomonas aeruginosa Consumption of Airway Metabolites Promotes Lung Infection

Abstract

Prevailing dogma indicates that the lung of cystic fibrosis (CF) individuals is infected by multiple pathogens due to the abundant accumulation of mucus, which traps most of inhaled organisms. However, this hypothesis does not explain how specific opportunists, like Pseudomonas aeruginosa, are selected in the CF lung to cause chronic disease. This strongly suggests that other factors than mucus are accrued in the human airway and might predispose to bacterial disease, especially by P. aeruginosa. In this review we discuss the role of macrophage metabolites, like succinate and itaconate, in P. aeruginosa pneumonia. We analyze how dysfunction of the CF transmembrane conductance regulator (CFTR) favors release of these metabolites into the infected airway, and how P. aeruginosa exploits these elements to induce transcriptomic and metabolic changes that increase its capacity to cause intractable disease. We describe the host and pathogen pathways associated with succinate and itaconate catabolism, mechanisms of bacterial adaptation to these determinants, and suggest how both experimental settings and future therapies should consider macrophage metabolites abundance to better study P. aeruginosa pathogenesis.

Carbohydrates Metabolic Signatures in Immune Cells: Response to Infection

“…The bacterial pathogen Pseudomonas aeruginosa , which causes cystic fibrosis, exploits metabolic elements such as succinate and itaconate, to induce metabolic and transcriptomic modulations in immune cells that increase its capacity to cause stubborn diseases ( 37 ). P. aeruginosa , through the process of catabolite repression, preferentially consumes succinate compared to other carbon sources ( 38 ).…”

Acetylation of CspC Controls the Las Quorum-Sensing System through Translational Regulation of rsaL in Pseudomonas aeruginosa

“…In response to oxidative stress and inflammation, macrophages and monocytes generate and release itaconate, an electrophilic α,β-unsaturated carboxylic acid that suppresses glycolysis, production of proinflammatory cytokines, including interleukin 1β (IL-1β) ( 65 ) and IL-6 ( 66 ), and reactive oxygen species ( 65 , 67 ). During lung infection with P. aeruginosa , itaconate is released into airways ( 68 , 69 ). P. aeruginosa isolates from CF patients have been shown to become adapted to utilize itaconate as a carbon source ( 39 ).…”

The opportunistic pathogen Pseudomonas aeruginosa exploits bacterial biotin synthesis pathway to benefit its infectivity

“…The successful infection of P. aeruginosa largely relies on the production of virulence-associated components (e.g., pyocyanin [7] and biofilms [8,9]) and its regulatory networks including two-component systems [10,11] and quorum sensing [9,12]. Essentially, P. aeruginosa dictates certain metabolic fluxes to circumvent host immune defenses and antimicrobial killing, and thus benefits its colonization and proliferation during infections [13,14]. In light the complex interplay of bacterial metabolisms occurs at infection sites, deep understanding of P. aeruginosa metabolic states [exemplified with biotin [15][16][17][18] and lipoic acid [19,20]] might offer alternative strategies to prevent and intervene the severe infections caused by this extracellular pathogen [14,21].…”

“…Essentially, P . aeruginosa dictates certain metabolic fluxes to circumvent host immune defenses and antimicrobial killing, and thus benefits its colonization and proliferation during infections [ 13 , 14 ]. In light that the complex interplay of bacterial metabolisms occurs at infection sites, deep understanding of P .…”

“…In light that the complex interplay of bacterial metabolisms occurs at infection sites, deep understanding of P . aeruginosa metabolic states [exemplified with biotin [ 15 – 18 ] and lipoic acid [ 19 , 20 ]] might offer alternative strategies to prevent and intervene the severe infections caused by this extracellular pathogen [ 14 , 21 ].…”