Quorum-Sensing Agr System of Staphylococcus aureus Primes Gene Expression for Protection From Lethal Oxidative Stress

Authors

Magdalena Podkowik
Andrew I Perault
Gregory Putzel
Andrew Pountain
Jisun Kim
Ashley L DuMont
Erin E Zwack
Robert J Ulrich
Theodora K Karagounis
Chunyi Zhou
Andreas F Haag
Julia Shenderovich
Gregory A Wasserman
Junbeom Kwon
John Chen
Anthony R Richardson
Jeffrey N Weiser
Carla R Nowosad
Desmond S Lun
Dane Parker
Alejandro Pironti
Xilin Zhao
Karl Drlica
Itai Yanai
Victor J Torres
Bo Shopsin

Publication Date

4-30-2024

Journal

eLife

Abstract

The agr quorum-sensing system links Staphylococcus aureus metabolism to virulence, in part by increasing bacterial survival during exposure to lethal concentrations of H2O2, 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 resulted in decreased ATP levels and growth, despite increased rates of respiration or fermentation at appropriate oxygen tensions, suggesting that Δagr cells undergo a shift towards a hyperactive metabolic state in response to diminished 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 Δagr strains to lethal H2O2 doses. Increased survival of wild-type agr cells during H2O2 exposure required sodA, which detoxifies superoxide. Additionally, pretreatment of S. aureus with respiration-reducing menadione protected Δagr cells from killing by H2O2. 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 (Cybb-/-) 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.

Keywords

Staphylococcus aureus, Oxidative Stress, Quorum Sensing, Bacterial Proteins, Animals, Trans-Activators, Gene Expression Regulation, Bacterial, Hydrogen Peroxide, Mice, Staphylococcal Infections, Microbial Viability, Reactive Oxygen Species, Gene Deletion

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