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.