Sequestration of the phagocyte metabolite itaconate by Pseudomonas aeruginosa RpoN promotes successful pulmonary infection.

Inhaled opportunistic pathogens such as Pseudomonas aeruginosa actively modify gene expression to meet the challenges of a new environment. In the infected airway the bacteria must respond to the immunometabolite itaconate, which is abundantly produced by macrophages and has anti-inflammatory and anti-oxidant functions that protect the host from airway damage and causes toxicity to bacteria. As a dicarboxylate that targets cysteine residues, itaconate can modify both bacterial and host proteins often altering metabolic activity. We demonstrate that itaconate promotes a global metabolic response in P. aeruginosa by enhancing the activity of the major alternative transcription factor RpoN. Itaconate is actively transported into the bacteria, induces σ54 rpoN expression and covalently binds cysteine residues 218 and 275 on RpoN helping to neutralize its toxicity. The S-itaconated RpoN exhibits a gain of function driving increased glucose catabolism and enhanced utilization of the bioenergetically efficient Entner-Doudoroff pathway. Thus, the accumulation of itaconate in the infected airway promotes the adaptation of P. aeruginosa to the lung by optimizing its metabolic activity and ability to cause pneumonia.