Inflammasome-mediated glucose limitation induces antibiotic tolerance in Staphylococcus aureus
Jenna E. Beam,
Nikki J. Wagner,
Kuan-Yi Lu,
Joshua B. Parsons,
Vance G. Fowler, Jr.,
Sarah E. Rowe,
Brian P. Conlon
Affiliations
Jenna E. Beam
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Nikki J. Wagner
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Kuan-Yi Lu
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Joshua B. Parsons
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Division of Infectious Diseases, Duke University School of Medicine, Durham, NC, USA
Vance G. Fowler, Jr.
Division of Infectious Diseases, Duke University School of Medicine, Durham, NC, USA
Sarah E. Rowe
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Brian P. Conlon
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Corresponding author
Summary: Staphylococcus aureus is a leading human pathogen that frequently causes relapsing infections. The failure of antibiotics to eradicate infection contributes to infection relapse. Host-pathogen interactions have a substantial impact on antibiotic susceptibility and the formation of antibiotic tolerant cells. In this study, we interrogate how a major S. aureus virulence factor, α-toxin, interacts with macrophages to alter the microenvironment of the pathogen, thereby influencing its susceptibility to antibiotics. We find α-toxin-mediated activation of the NLRP3 inflammasome induces antibiotic tolerance. Induction of tolerance is driven by increased glycolysis in the host cells, resulting in glucose limitation and ATP depletion in S. aureus. Additionally, inhibition of NLRP3 activation improves antibiotic efficacy in vitro and in vivo, suggesting that this strategy has potential as a host-directed therapeutic to improve outcomes. Our findings identify interactions between S. aureus and the host that result in metabolic crosstalk that can determine the outcome of antimicrobial therapy.
