Quorum-sensing agr system of Staphylococcus aureus primes gene expression for protection from lethal oxidative stress

Author:

Podkowik Magdalena12,Perault Andrew I.23,Putzel Gregory234,Pountain Andrew5,Kim Jisun6,Dumont Ashley3,Zwack Erin3,Ulrich Robert J.1,Karagounis Theodora K.27,Zhou Chunyi12,Haag Andreas F.8ORCID,Shenderovich Julia23,Wasserman Gregory A.9,Kwon Junbeom1,Chen John10,Richardson Anthony R.11,Weiser Jeffrey N.3ORCID,Nowosad Carla R.12,Lun Desmond S.13,Parker Dane6,Pironti Alejandro234,Zhao Xilin14,Drlica Karl1516,Yanai Itai517,Torres Victor J.23,Shopsin Bo123

Affiliation:

1. Department of Medicine, Division of Infectious Diseases, NYU Grossman School of Medicine

2. Antimicrobial-Resistant Pathogens Program, New York University School of Medicine

3. Department of Microbiology, NYU Grossman School of Medicine

4. Microbial Computational Genomic Core Lab, NYU Grossman School of Medicine

5. Institute for Systems Genetics; NYU Grossman School of Medicine

6. Department of Pathology, Immunology and Laboratory Medicine, Center for Immunity and Inflammation, Rutgers New Jersey Medical School Cancer Center

7. Ronald O. Perelman Department of Dermatology; NYU Grossman School of Medicine

8. School of Medicine, University of St Andrews

9. Department of Surgery, Northwell Health Lenox Hill Hospital

10. Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore

11. Department of Microbiology and Molecular Genetics, University of Pittsburgh

12. Department of Pathology, NYU Grossman School of Medicine

13. Center for Computational and Integrative Biology and Department of Computer Science, Rutgers University

14. State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University

15. Public Health Research Institute, New Jersey Medical School, Rutgers University

16. Department of Microbiology, Biochemistry & Molecular Genetics, New Jersey Medical School, Rutgers University

17. Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine

Abstract

The agr quorum-sensing system links Staphylococcus aureus metabolism to virulence, in part by increasing bacterial survival during exposure to lethal concentrations of H 2 O 2 , a crucial host defense against S. aureus . We now report that protection by agr surprisingly extends beyond post-exponential growth to the exit from stationary phase when the agr system is no longer turned on. Thus, agr can be considered a constitutive protective factor. Deletion of agr increased both respiration and aerobic fermentation but decreased ATP levels and growth, suggesting that Δ agr cells assume a hyperactive metabolic state in response to reduced metabolic efficiency. As expected from increased respiratory gene expression, reactive oxygen species (ROS) accumulated more in the agr mutant than in wild-type cells, thereby explaining elevated susceptibility of Δ agr strains to lethal H 2 O 2 doses. Increased survival of wild-type agr cells during H 2 O 2 exposure required sodA , which detoxifies superoxide. Additionally, pretreatment of S. aureus with respiration-reducing menadione protected Δ agr cells from killing by H 2 O 2 . Thus, genetic deletion and pharmacologic experiments indicate that agr helps control endogenous ROS, thereby providing resilience against exogenous ROS. The long-lived “memory” of agr -mediated protection, which is uncoupled from agr activation kinetics, increased hematogenous dissemination to certain tissues during sepsis in ROS-producing, wild-type mice but not ROS-deficient (Nox2 −/− ) mice. These results demonstrate the importance of protection that anticipates impending ROS-mediated immune attack. The ubiquity of quorum sensing suggests that it protects many bacterial species from oxidative damage.

Publisher

eLife Sciences Publications, Ltd

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