Staphylococcus aureus stimulates neutrophil itaconate production that suppresses the oxidative burst
Kira L. Tomlinson, Sebastián Riquelme-Barrios, Swikrity Upadhyay Baskota, Marija Drikic, Ian R. Monk, Timothy P. Stinear, Ian A. Lewis, Alice Prince
Abstract
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 evade immune clearance. 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 the lung from excessive inflammation but compromises bacterial clearance. S. aureus is thus able to evade the innate immune response by targeting neutrophil metabolism and inducing the production of the anti-inflammatory metabolite itaconate.