Staphylococcus aureus stimulates neutrophil itaconate production that suppresses the oxidative burst
Kira L. Tomlinson,
Sebastián A. Riquelme,
Swikrity Upadhyay Baskota,
Marija Drikic,
Ian R. Monk,
Timothy P. Stinear,
Ian A. Lewis,
Alice S. Prince
Affiliations
Kira L. Tomlinson
Department of Pediatrics, Columbia University, New York, NY 10032, USA
Sebastián A. Riquelme
Department of Pediatrics, Columbia University, New York, NY 10032, USA
Swikrity Upadhyay Baskota
Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA
Marija Drikic
Department of Biological Sciences, University of Calgary, Calgary, AB T2N 1N4, Canada
Ian R. Monk
Department of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia
Timothy P. Stinear
Department of Microbiology and Immunology, The University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia
Ian A. Lewis
Department of Biological Sciences, University of Calgary, Calgary, AB T2N 1N4, Canada
Alice S. Prince
Department of Pediatrics, Columbia University, New York, NY 10032, USA; Corresponding author
Summary: 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.
