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.

Keywords: CFTR; PTEN; Pseudomonas aeruginosa; cystic fibrosis; immunometabolism; inflammation; itaconate; succinate.

Figure 1

The CFTR-PTEN complex regulates macrophage metabolism and release of immunometabolites. (A) During LPS recognition by TLR4, macrophages activate PI3K-Akt-mTOR signaling and glycolysis. The CFTR-PTEN complex regulates this process by inhibiting PI3K function. In parallel, TLR4-LPS interaction promotes anerplerosis, which replenishes the host mitochondria with succinate. Succinate is oxidized by succinate dehydrogenase (SDH) to fumarate, which produces bactericidal ROS. Pro-oxidant SDH activity is regulated by IRG1, which produces itaconate that competes with succinate for the active site of SDH. (B) In the absence of the CFTR-PTEN complex, glycolysis is overactivated, as well as succinate oxidation. Itaconate is overproduced to compensate for succinate oxidation, leading to both succinate and itaconate accumulation in the mitochondria. Both metabolites are abundantly released out of the cell, where they can be assimilated by Pseudomonas aeruginosa. These organisms also sense ROS, which promotes adaptive changes like biofilm formation.

Figure 2

Itaconate controls both host and bacteria metabolism. Itaconate, synthetized by mitochondrial IRG1, inhibits host cell metabolism at different levels. Itaconate can block GADPH, aldolase and the NLRP3-NEK7 complex, which participate in pro-inflammatory signaling. Itaconate also interferes with SDH function, which is required to promote IL-1β synthesis. Once secreted, itaconate blocks the glyoxylate shunt pathway in P. aeruginosa by blocking aceA activity. In S. aureus, itaconate inhibits aldolase, suppressing glycolysis and bacterial proliferation.

Figure 3

CF host-adapted P. aeruginosa isolates evoke itaconate release by airway macrophages. (A) In contrast with environmental P. aeruginosa strains that produce pro-IL-1β factors like lipopolysaccharides (LPS), type III secretion system’s toxins, and flagella, isolates recovered from the CF airway mostly conserve EPSs production, like alginate. (B) CF host-adapted P. aeruginosa isolates promote abundant macrophage itaconate signaling and fail to induce the succinate-HIF-1α-NLRP3-IL-1β axis.