Staphylococcus aureus Multiplexes Death-Effector Deoxyribonucleosides to Neutralize Phagocytes.

Autor:	Tantawy E; Research Group Pathogenesis of Bacterial Infections, TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture Between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany.; Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany., Schwermann N; Research Group Pathogenesis of Bacterial Infections, TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture Between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany.; Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany., Ostermeier T; Research Group Pathogenesis of Bacterial Infections, TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture Between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany.; Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany., Garbe A; Research Core Unit Metabolomics, Hannover Medical School, Hannover, Germany., Bähre H; Research Core Unit Metabolomics, Hannover Medical School, Hannover, Germany., Vital M; Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany., Winstel V; Research Group Pathogenesis of Bacterial Infections, TWINCORE, Centre for Experimental and Clinical Infection Research, a Joint Venture Between the Hannover Medical School and the Helmholtz Centre for Infection Research, Hannover, Germany.; Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2022 Mar 10; Vol. 13, pp. 847171. Date of Electronic Publication: 2022 Mar 10 (Print Publication: 2022).
DOI:	10.3389/fimmu.2022.847171
Abstrakt:	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. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2022 Tantawy, Schwermann, Ostermeier, Garbe, Bähre, Vital and Winstel.)
Databáze:	MEDLINE
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