Staphylococcus aureus stimulates neutrophil itaconate production that suppresses the oxidative burst

Neutrophils are critical in the host defense against Staphylococcus aureus, a major human pathogen. However, even in the setting of a robust neutrophil response, S. aureus can cause persistent infection. Here we demonstrate that S. aureus impairs neutrophil function by triggering the production of the anti-inflammatory metabolite, itaconate. The enzyme that synthesizes itaconate, Irg1, is selectively expressed in neutrophils during S. aureus pneumonia. Itaconate inhibits neutrophil glycolysis and oxidative burst, which impairs survival and bacterial killing. In a murine pneumonia model, neutrophil Irg1 expression protects critical lung cell populations from oxidative stress but compromises bacterial clearance. S. aureus is thus able to evade innate immune clearance by targeting neutrophil metabolism and inducing the production of the antiinflammatory metabolite itaconate. Overall design: 8-week old WT and Irg1-/- C57BL/6NJ mice were intranasally infected with 2 x 10^7 USA300 LAC in 50 mL PBS or treated with PBS alone; 24 hours after infection, the lungs were harvested and subjected to scRNA-seq on the 10X Genomics platform.