<named-content content-type="genus-species">Staphylococcus aureus</named-content> Exploits the Host Apoptotic Pathway To Persist during Infection

ABSTRACT Staphylococcus aureus is a deadly pathogen that causes fatal diseases in humans. During infection, S. aureus secretes nuclease (Nuc) and adenosine synthase A (AdsA) to generate cytotoxic deoxyadenosine (dAdo) from neutrophil extracellular traps which triggers noninflammatory apoptosis in ma...

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Autores principales:	Volker Winstel, Olaf Schneewind, Dominique Missiakas
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	Staphylococcus aureus adenosine synthase A (AdsA) caspase-3 deoxyadenosine neutrophil extracellular traps (NETs) Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/96ced280a7214751a3686edfdb0d8892
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spelling	oai:doaj.org-article:96ced280a7214751a3686edfdb0d88922021-11-15T15:54:45Z<named-content content-type="genus-species">Staphylococcus aureus</named-content> Exploits the Host Apoptotic Pathway To Persist during Infection10.1128/mBio.02270-192150-7511https://doaj.org/article/96ced280a7214751a3686edfdb0d88922019-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02270-19https://doaj.org/toc/2150-7511ABSTRACT Staphylococcus aureus is a deadly pathogen that causes fatal diseases in humans. During infection, S. aureus secretes nuclease (Nuc) and adenosine synthase A (AdsA) to generate cytotoxic deoxyadenosine (dAdo) from neutrophil extracellular traps which triggers noninflammatory apoptosis in macrophages. In this manner, replicating staphylococci escape phagocytic killing without alerting the immune system. Here, we show that mice lacking caspase-3 in immune cells exhibit increased resistance toward S. aureus. Caspase-3-deficient macrophages are resistant to staphylococcal dAdo and gain access to abscess lesions to promote bacterial clearance in infected animals. We identify specific single nucleotide polymorphisms in CASP3 as candidate human resistance alleles that protect macrophages from S. aureus-derived dAdo, raising the possibility that the allelic repertoire of caspase-3 may contribute to the outcome of S. aureus infections in humans. IMPORTANCE Caspase-3 controls the apoptotic pathway, a form of programmed cell death designed to be immunologically silent. Polymorphisms leading to reduced caspase-3 activity are associated with variable effects on tumorigenesis and yet arise frequently. Staphylococcus aureus is a human commensal and a frequent cause of soft tissue and bloodstream infections. Successful commensalism and virulence can be explained by the secretion of a plethora of immune evasion factors. One such factor, AdsA, destroys phagocytic cells by exploiting the apoptotic pathway. However, human CASP3 variants with loss-of-function alleles shield phagocytes from AdsA-mediated killing. This finding raises the possibility that some caspase-3 alleles may arise from exposure to S. aureus and other human pathogens that exploit the apoptotic pathway for infection.Volker WinstelOlaf SchneewindDominique MissiakasAmerican Society for MicrobiologyarticleStaphylococcus aureusadenosine synthase A (AdsA)caspase-3deoxyadenosineneutrophil extracellular traps (NETs)MicrobiologyQR1-502ENmBio, Vol 10, Iss 6 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Staphylococcus aureus adenosine synthase A (AdsA) caspase-3 deoxyadenosine neutrophil extracellular traps (NETs) Microbiology QR1-502
spellingShingle	Staphylococcus aureus adenosine synthase A (AdsA) caspase-3 deoxyadenosine neutrophil extracellular traps (NETs) Microbiology QR1-502 Volker Winstel Olaf Schneewind Dominique Missiakas <named-content content-type="genus-species">Staphylococcus aureus</named-content> Exploits the Host Apoptotic Pathway To Persist during Infection
description	ABSTRACT Staphylococcus aureus is a deadly pathogen that causes fatal diseases in humans. During infection, S. aureus secretes nuclease (Nuc) and adenosine synthase A (AdsA) to generate cytotoxic deoxyadenosine (dAdo) from neutrophil extracellular traps which triggers noninflammatory apoptosis in macrophages. In this manner, replicating staphylococci escape phagocytic killing without alerting the immune system. Here, we show that mice lacking caspase-3 in immune cells exhibit increased resistance toward S. aureus. Caspase-3-deficient macrophages are resistant to staphylococcal dAdo and gain access to abscess lesions to promote bacterial clearance in infected animals. We identify specific single nucleotide polymorphisms in CASP3 as candidate human resistance alleles that protect macrophages from S. aureus-derived dAdo, raising the possibility that the allelic repertoire of caspase-3 may contribute to the outcome of S. aureus infections in humans. IMPORTANCE Caspase-3 controls the apoptotic pathway, a form of programmed cell death designed to be immunologically silent. Polymorphisms leading to reduced caspase-3 activity are associated with variable effects on tumorigenesis and yet arise frequently. Staphylococcus aureus is a human commensal and a frequent cause of soft tissue and bloodstream infections. Successful commensalism and virulence can be explained by the secretion of a plethora of immune evasion factors. One such factor, AdsA, destroys phagocytic cells by exploiting the apoptotic pathway. However, human CASP3 variants with loss-of-function alleles shield phagocytes from AdsA-mediated killing. This finding raises the possibility that some caspase-3 alleles may arise from exposure to S. aureus and other human pathogens that exploit the apoptotic pathway for infection.
format	article
author	Volker Winstel Olaf Schneewind Dominique Missiakas
author_facet	Volker Winstel Olaf Schneewind Dominique Missiakas
author_sort	Volker Winstel
title	<named-content content-type="genus-species">Staphylococcus aureus</named-content> Exploits the Host Apoptotic Pathway To Persist during Infection
title_short	<named-content content-type="genus-species">Staphylococcus aureus</named-content> Exploits the Host Apoptotic Pathway To Persist during Infection
title_full	<named-content content-type="genus-species">Staphylococcus aureus</named-content> Exploits the Host Apoptotic Pathway To Persist during Infection
title_fullStr	<named-content content-type="genus-species">Staphylococcus aureus</named-content> Exploits the Host Apoptotic Pathway To Persist during Infection
title_full_unstemmed	<named-content content-type="genus-species">Staphylococcus aureus</named-content> Exploits the Host Apoptotic Pathway To Persist during Infection
title_sort	<named-content content-type="genus-species">staphylococcus aureus</named-content> exploits the host apoptotic pathway to persist during infection
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/96ced280a7214751a3686edfdb0d8892
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<named-content content-type="genus-species">Staphylococcus aureus</named-content> Exploits the Host Apoptotic Pathway To Persist during Infection

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