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Staphylococcus aureus multiplexes death-effector deoxyribonucleosides to neutralize phagocytes

ABSTRACT: Staphylococcus aureus multiplexes death-effector deoxyribonucleosides to neutralize phagocytes

PROVIDER: PRJEB50054 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	ERR7996874_1.fastq.gz	Fastqsanger.gz
	ERR7996874_2.fastq.gz	Fastqsanger.gz
	ERR7996875_1.fastq.gz	Fastqsanger.gz
	ERR7996875_2.fastq.gz	Fastqsanger.gz
	ERR7996876_1.fastq.gz	Fastqsanger.gz

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<i>Staphylococcus aureus</i> Multiplexes Death-Effector Deoxyribonucleosides to Neutralize Phagocytes.

Project description:Adenosine synthase A (AdsA) is a key virulence factor of Staphylococcus aureus, a dangerous microbe that causes fatal diseases in humans. Together with staphylococcal nuclease, AdsA generates deoxyadenosine (dAdo) from neutrophil extracellular DNA traps thereby igniting caspase-3-dependent cell death in host immune cells that aim at penetrating infectious foci. Powered by a multi-technological approach, we here illustrate that the enzymatic activity of AdsA in abscess-mimicking microenvironments is not restricted to the biogenesis of dAdo but rather comprises excessive biosynthesis of deoxyguanosine (dGuo), a cytotoxic deoxyribonucleoside generated by S. aureus to eradicate macrophages of human and animal origin. Based on a genome-wide CRISPR-Cas9 knock-out screen, we further demonstrate that dGuo-induced cytotoxicity in phagocytes involves targeting of the mammalian purine salvage pathway-apoptosis axis, a signaling cascade that is concomitantly stimulated by staphylococcal dAdo. Strikingly, synchronous targeting of this route by AdsA-derived dGuo and dAdo boosts macrophage cell death, indicating that S. aureus multiplexes death-effector deoxyribonucleosides to maximize intra-host survival. Overall, these data provide unique insights into the cunning lifestyle of a deadly pathogen and may help to design therapeutic intervention strategies to combat multidrug-resistant staphylococci.

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