CpaA Is a Glycan-Specific Adamalysin-like Protease Secreted by <named-content content-type="genus-species">Acinetobacter baumannii</named-content> That Inactivates Coagulation Factor XII

ABSTRACT Antibiotic-resistant Acinetobacter baumannii is increasingly recognized as a cause of difficult-to-treat nosocomial infections, including pneumonia, wound infections, and bacteremia. Previous studies have demonstrated that the metalloprotease CpaA contributes to virulence and prolongs clott...

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Autores principales:	Ursula Waack, Mark Warnock, Andrew Yee, Zachary Huttinger, Sara Smith, Ayush Kumar, Alban Deroux, David Ginsburg, Harry L. T. Mobley, Daniel A. Lawrence, Maria Sandkvist
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2018
Materias:	Acinetobacter baumannii CpaA factor XII O-linked glycosylation metalloprotease thrombosis Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/d973548e5bd446dbbe654031c2645100
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spelling	oai:doaj.org-article:d973548e5bd446dbbe654031c26451002021-11-15T15:52:19ZCpaA Is a Glycan-Specific Adamalysin-like Protease Secreted by <named-content content-type="genus-species">Acinetobacter baumannii</named-content> That Inactivates Coagulation Factor XII10.1128/mBio.01606-182150-7511https://doaj.org/article/d973548e5bd446dbbe654031c26451002018-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01606-18https://doaj.org/toc/2150-7511ABSTRACT Antibiotic-resistant Acinetobacter baumannii is increasingly recognized as a cause of difficult-to-treat nosocomial infections, including pneumonia, wound infections, and bacteremia. Previous studies have demonstrated that the metalloprotease CpaA contributes to virulence and prolongs clotting time when added to human plasma as measured by the activated partial thromboplastin time (aPTT) assay. Here, we show that CpaA interferes with the intrinsic coagulation pathway, also called the contact activation system, in human as well as murine plasma, but has no discernible effect on the extrinsic pathway. By utilizing a modified aPTT assay, we demonstrate that coagulation factor XII (fXII) is a target of CpaA. In addition, we map the cleavage by CpaA to two positions, 279-280 and 308-309, within the highly glycosylated proline-rich region of human fXII, and show that cleavage at the 308-309 site is responsible for inactivation of fXII. At both sites, cleavage occurs between proline and an O-linked glycosylated threonine, and deglycosylation of fXII prevents cleavage by CpaA. Consistent with this, mutant fXII (fXII-Thr309Lys) from patients with hereditary angioedema type III (HAEIII) is protected from CpaA inactivation. This raises the possibility that individuals with HAEIII who harbor this mutation may be partially protected from A. baumannii infection if CpaA contributes to human disease. By inactivating fXII, CpaA may attenuate important antimicrobial defense mechanisms such as intravascular thrombus formation, thus allowing A. baumannii to disseminate. IMPORTANCE Ventilator-associated pneumonia and catheter-related bacteremia are the most common and severe infections caused by Acinetobacter baumannii. Besides the capsule, lipopolysaccharides, and the outer membrane porin OmpA, little is known about the contribution of secreted proteins to A. baumannii survival in vivo. Here we focus on CpaA, a potentially recently acquired virulence factor that inhibits blood coagulation in vitro. We identify coagulation factor XII as a target of CpaA, map the cleavage sites, and show that glycosylation is a prerequisite for CpaA-mediated inactivation of factor XII. We propose adding CpaA to a small, but growing list of bacterial proteases that are specific for highly glycosylated components of the host defense system.Ursula WaackMark WarnockAndrew YeeZachary HuttingerSara SmithAyush KumarAlban DerouxDavid GinsburgHarry L. T. MobleyDaniel A. LawrenceMaria SandkvistAmerican Society for MicrobiologyarticleAcinetobacter baumanniiCpaAfactor XIIO-linked glycosylationmetalloproteasethrombosisMicrobiologyQR1-502ENmBio, Vol 9, Iss 6 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Acinetobacter baumannii CpaA factor XII O-linked glycosylation metalloprotease thrombosis Microbiology QR1-502
spellingShingle	Acinetobacter baumannii CpaA factor XII O-linked glycosylation metalloprotease thrombosis Microbiology QR1-502 Ursula Waack Mark Warnock Andrew Yee Zachary Huttinger Sara Smith Ayush Kumar Alban Deroux David Ginsburg Harry L. T. Mobley Daniel A. Lawrence Maria Sandkvist CpaA Is a Glycan-Specific Adamalysin-like Protease Secreted by <named-content content-type="genus-species">Acinetobacter baumannii</named-content> That Inactivates Coagulation Factor XII
description	ABSTRACT Antibiotic-resistant Acinetobacter baumannii is increasingly recognized as a cause of difficult-to-treat nosocomial infections, including pneumonia, wound infections, and bacteremia. Previous studies have demonstrated that the metalloprotease CpaA contributes to virulence and prolongs clotting time when added to human plasma as measured by the activated partial thromboplastin time (aPTT) assay. Here, we show that CpaA interferes with the intrinsic coagulation pathway, also called the contact activation system, in human as well as murine plasma, but has no discernible effect on the extrinsic pathway. By utilizing a modified aPTT assay, we demonstrate that coagulation factor XII (fXII) is a target of CpaA. In addition, we map the cleavage by CpaA to two positions, 279-280 and 308-309, within the highly glycosylated proline-rich region of human fXII, and show that cleavage at the 308-309 site is responsible for inactivation of fXII. At both sites, cleavage occurs between proline and an O-linked glycosylated threonine, and deglycosylation of fXII prevents cleavage by CpaA. Consistent with this, mutant fXII (fXII-Thr309Lys) from patients with hereditary angioedema type III (HAEIII) is protected from CpaA inactivation. This raises the possibility that individuals with HAEIII who harbor this mutation may be partially protected from A. baumannii infection if CpaA contributes to human disease. By inactivating fXII, CpaA may attenuate important antimicrobial defense mechanisms such as intravascular thrombus formation, thus allowing A. baumannii to disseminate. IMPORTANCE Ventilator-associated pneumonia and catheter-related bacteremia are the most common and severe infections caused by Acinetobacter baumannii. Besides the capsule, lipopolysaccharides, and the outer membrane porin OmpA, little is known about the contribution of secreted proteins to A. baumannii survival in vivo. Here we focus on CpaA, a potentially recently acquired virulence factor that inhibits blood coagulation in vitro. We identify coagulation factor XII as a target of CpaA, map the cleavage sites, and show that glycosylation is a prerequisite for CpaA-mediated inactivation of factor XII. We propose adding CpaA to a small, but growing list of bacterial proteases that are specific for highly glycosylated components of the host defense system.
format	article
author	Ursula Waack Mark Warnock Andrew Yee Zachary Huttinger Sara Smith Ayush Kumar Alban Deroux David Ginsburg Harry L. T. Mobley Daniel A. Lawrence Maria Sandkvist
author_facet	Ursula Waack Mark Warnock Andrew Yee Zachary Huttinger Sara Smith Ayush Kumar Alban Deroux David Ginsburg Harry L. T. Mobley Daniel A. Lawrence Maria Sandkvist
author_sort	Ursula Waack
title	CpaA Is a Glycan-Specific Adamalysin-like Protease Secreted by <named-content content-type="genus-species">Acinetobacter baumannii</named-content> That Inactivates Coagulation Factor XII
title_short	CpaA Is a Glycan-Specific Adamalysin-like Protease Secreted by <named-content content-type="genus-species">Acinetobacter baumannii</named-content> That Inactivates Coagulation Factor XII
title_full	CpaA Is a Glycan-Specific Adamalysin-like Protease Secreted by <named-content content-type="genus-species">Acinetobacter baumannii</named-content> That Inactivates Coagulation Factor XII
title_fullStr	CpaA Is a Glycan-Specific Adamalysin-like Protease Secreted by <named-content content-type="genus-species">Acinetobacter baumannii</named-content> That Inactivates Coagulation Factor XII
title_full_unstemmed	CpaA Is a Glycan-Specific Adamalysin-like Protease Secreted by <named-content content-type="genus-species">Acinetobacter baumannii</named-content> That Inactivates Coagulation Factor XII
title_sort	cpaa is a glycan-specific adamalysin-like protease secreted by <named-content content-type="genus-species">acinetobacter baumannii</named-content> that inactivates coagulation factor xii
publisher	American Society for Microbiology
publishDate	2018
url	https://doaj.org/article/d973548e5bd446dbbe654031c2645100
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CpaA Is a Glycan-Specific Adamalysin-like Protease Secreted by <named-content content-type="genus-species">Acinetobacter baumannii</named-content> That Inactivates Coagulation Factor XII

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