Staphylococcus aureus Exploits the Host Apoptotic Pathway To Persist during Infection

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 freque...

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Main Authors: Volker Winstel, Olaf Schneewind, Dominique Missiakas
Format: Article
Language:English
Published: American Society for Microbiology 2019-11-01
Series:mBio
Subjects:
Online Access:https://doi.org/10.1128/mBio.02270-19
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spelling doaj-96116d89a9d742e78281597ee806214a2021-07-02T12:40:01ZengAmerican Society for MicrobiologymBio2150-75112019-11-01106e02270-1910.1128/mBio.02270-19Staphylococcus aureus Exploits the Host Apoptotic Pathway To Persist during InfectionVolker WinstelOlaf SchneewindDominique MissiakasCaspase-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.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.https://doi.org/10.1128/mBio.02270-19staphylococcus aureusadenosine synthase a (adsa)caspase-3deoxyadenosineneutrophil extracellular traps (nets)
collection DOAJ
language English
format Article
sources DOAJ
author Volker Winstel
Olaf Schneewind
Dominique Missiakas
spellingShingle Volker Winstel
Olaf Schneewind
Dominique Missiakas
Staphylococcus aureus Exploits the Host Apoptotic Pathway To Persist during Infection
mBio
staphylococcus aureus
adenosine synthase a (adsa)
caspase-3
deoxyadenosine
neutrophil extracellular traps (nets)
author_facet Volker Winstel
Olaf Schneewind
Dominique Missiakas
author_sort Volker Winstel
title Staphylococcus aureus Exploits the Host Apoptotic Pathway To Persist during Infection
title_short Staphylococcus aureus Exploits the Host Apoptotic Pathway To Persist during Infection
title_full Staphylococcus aureus Exploits the Host Apoptotic Pathway To Persist during Infection
title_fullStr Staphylococcus aureus Exploits the Host Apoptotic Pathway To Persist during Infection
title_full_unstemmed Staphylococcus aureus Exploits the Host Apoptotic Pathway To Persist during Infection
title_sort staphylococcus aureus exploits the host apoptotic pathway to persist during infection
publisher American Society for Microbiology
series mBio
issn 2150-7511
publishDate 2019-11-01
description 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.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.
topic staphylococcus aureus
adenosine synthase a (adsa)
caspase-3
deoxyadenosine
neutrophil extracellular traps (nets)
url https://doi.org/10.1128/mBio.02270-19
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AT olafschneewind staphylococcusaureusexploitsthehostapoptoticpathwaytopersistduringinfection
AT dominiquemissiakas staphylococcusaureusexploitsthehostapoptoticpathwaytopersistduringinfection
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