Staphylococcus aureus Uses the GraXRS Regulatory System To Sense and Adapt to the Acidified Phagolysosome in Macrophages

MBio
Ronald S FlannaganDavid E Heinrichs

Abstract

Macrophages are critical to innate immunity due to their ability to phagocytose bacteria. The macrophage phagolysosome is a highly acidic organelle with potent antimicrobial properties, yet remarkably, ingested Staphylococcus aureus replicates within this niche. Herein we demonstrate that S. aureus requires the GraXRS regulatory system for growth within this niche, while the SaeRS and AgrAC two-component regulatory systems and the α-phenol soluble modulins are dispensable. Importantly, we find that it is exposure to acidic pH that is required for optimal growth of S. aureus inside fully acidified macrophage phagolysosomes. Exposure of S. aureus to acidic pH evokes GraS signaling, which in turn elicits an adaptive response that endows the bacteria with increased resistance to antimicrobial effectors, such as antimicrobial peptides, encountered inside macrophage phagolysosomes. Notably, pH-dependent induction of antimicrobial peptide resistance in S. aureus requires the GraS sensor kinase. GraS and MprF, a member of the GraS regulon, play an important role for bacterial survival in the acute stages of systemic infection, where in murine models of infection, S. aureus resides within liver-resident Kupffer cells. We conclude that G...Continue Reading

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Citations

Dec 24, 2018·Cellular Microbiology·Adriana Moldovan, Martin J Fraunholz
Nov 26, 2019·Molecular Microbiology·Arturo Casadevall, Ferric C Fang
Oct 17, 2019·MBio·Jennifer L KraussDeborah J Veis
Jan 9, 2019·Frontiers in Microbiology·Ronald S Flannagan, David E Heinrichs
Nov 27, 2019·Nature Chemical Biology·Omar M El-HalfawyEric D Brown
Jul 7, 2020·Archives of Pharmacal Research·JuOae ChangWonsik Lee
Jan 27, 2021·Blood Advances·Ronald S FlannaganDavid E Heinrichs
Feb 6, 2021·Frontiers in Immunology·Grace R PidwillSimon J Foster
Nov 24, 2020·Virulence·Elisa J M RaineriJan Maarten van Dijl
May 4, 2020·Current Opinion in Microbiology·Chunyi Zhou, Paul D Fey
Jul 17, 2021·Advanced Drug Delivery Reviews·Wei YanSharon S Y Leung
Aug 10, 2021·Infection and Immunity·Misu A SansonAnthony R Flores
Oct 28, 2021·Microbiology Spectrum·Viktoria RungelrathFrank R DeLeo

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Methods Mentioned

BETA
fluorescence microscopy
BioScreen
fluorescence imaging

Software Mentioned

GraXRS
Leica LAS X
GraphPad Prism
ImageJ

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