CspA from <named-content content-type="genus-species">Borrelia burgdorferi</named-content> Inhibits the Terminal Complement Pathway

ABSTRACT In order to survive and persist in an immunocompetent human host, Borrelia burgdorferi controls the human immune attack and blocks the damaging effects of the activated complement system. These Gram-negative spirochetes use CspA (CRASP-1) and four additional immune evasion proteins to bind...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Teresia Hallström, Corinna Siegel, Matthias Mörgelin, Peter Kraiczy, Christine Skerka, Peter F. Zipfel
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2013
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/ab3a9787581841e9812f351fc7ac1be6
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:ab3a9787581841e9812f351fc7ac1be6
record_format	dspace
spelling	oai:doaj.org-article:ab3a9787581841e9812f351fc7ac1be62021-11-15T15:43:08ZCspA from <named-content content-type="genus-species">Borrelia burgdorferi</named-content> Inhibits the Terminal Complement Pathway10.1128/mBio.00481-132150-7511https://doaj.org/article/ab3a9787581841e9812f351fc7ac1be62013-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00481-13https://doaj.org/toc/2150-7511ABSTRACT In order to survive and persist in an immunocompetent human host, Borrelia burgdorferi controls the human immune attack and blocks the damaging effects of the activated complement system. These Gram-negative spirochetes use CspA (CRASP-1) and four additional immune evasion proteins to bind combinations of human plasma regulators, including factor H, factor H-like protein 1 (FHL-1), complement factor H-related protein 1 (CFHR1), CFHR2, CFHR5, and plasminogen. As many microbial immune evasion proteins have multiple functions, we hypothesized that CspA has additional roles in complement or immune control. Here, we identify CspA as a terminal complement inhibitor. Borrelial CspA binds the human terminal complement components C7 and C9 and blocks assembly and membrane insertion of the terminal complement complex (TCC). CspA inhibits TCC assembly at the level of C7, as revealed by hemolytic assays, and inhibits polymerization of C9. CspA, when ectopically expressed on the surface of serum-sensitive Borrelia garinii, blocks TCC assembly on the level of C7 and induces serum resistance in the transformed bacteria. This CspA-mediated serum resistance and terminal complement pathway inhibition allow B. burgdorferi to survive in the hostile environment of human plasma. IMPORTANCE The present study defines a new mechanism by which the pathogenic bacterium Borrelia burgdorferi controls the terminal complement pathway of the human host to survive in human serum. The borrelial CspA binds to terminal pathway proteins C7 and C9 and inhibits the terminal complement pathway at the step of C7 and thereby inhibits terminal complement complex (TCC) assembly and membrane insertion. CspA blocks TCC assembly and insertion when expressed at the bacterial surface. CspA is the first TCC inhibitor cloned and functionally characterized from a Gram-negative bacterium. This identification of a bacterial TCC inhibitor of pathogen origin expands our knowledge of complement evasion of pathogenic bacteria and shows that pathogenic bacteria target the terminal pathway of complement. Thus, CspA as a central microbial virulence factor can represent an interesting biomarker and a target to develop new therapeutics and vaccines against borreliae.Teresia HallströmCorinna SiegelMatthias MörgelinPeter KraiczyChristine SkerkaPeter F. ZipfelAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 4, Iss 4 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Teresia Hallström Corinna Siegel Matthias Mörgelin Peter Kraiczy Christine Skerka Peter F. Zipfel CspA from <named-content content-type="genus-species">Borrelia burgdorferi</named-content> Inhibits the Terminal Complement Pathway
description	ABSTRACT In order to survive and persist in an immunocompetent human host, Borrelia burgdorferi controls the human immune attack and blocks the damaging effects of the activated complement system. These Gram-negative spirochetes use CspA (CRASP-1) and four additional immune evasion proteins to bind combinations of human plasma regulators, including factor H, factor H-like protein 1 (FHL-1), complement factor H-related protein 1 (CFHR1), CFHR2, CFHR5, and plasminogen. As many microbial immune evasion proteins have multiple functions, we hypothesized that CspA has additional roles in complement or immune control. Here, we identify CspA as a terminal complement inhibitor. Borrelial CspA binds the human terminal complement components C7 and C9 and blocks assembly and membrane insertion of the terminal complement complex (TCC). CspA inhibits TCC assembly at the level of C7, as revealed by hemolytic assays, and inhibits polymerization of C9. CspA, when ectopically expressed on the surface of serum-sensitive Borrelia garinii, blocks TCC assembly on the level of C7 and induces serum resistance in the transformed bacteria. This CspA-mediated serum resistance and terminal complement pathway inhibition allow B. burgdorferi to survive in the hostile environment of human plasma. IMPORTANCE The present study defines a new mechanism by which the pathogenic bacterium Borrelia burgdorferi controls the terminal complement pathway of the human host to survive in human serum. The borrelial CspA binds to terminal pathway proteins C7 and C9 and inhibits the terminal complement pathway at the step of C7 and thereby inhibits terminal complement complex (TCC) assembly and membrane insertion. CspA blocks TCC assembly and insertion when expressed at the bacterial surface. CspA is the first TCC inhibitor cloned and functionally characterized from a Gram-negative bacterium. This identification of a bacterial TCC inhibitor of pathogen origin expands our knowledge of complement evasion of pathogenic bacteria and shows that pathogenic bacteria target the terminal pathway of complement. Thus, CspA as a central microbial virulence factor can represent an interesting biomarker and a target to develop new therapeutics and vaccines against borreliae.
format	article
author	Teresia Hallström Corinna Siegel Matthias Mörgelin Peter Kraiczy Christine Skerka Peter F. Zipfel
author_facet	Teresia Hallström Corinna Siegel Matthias Mörgelin Peter Kraiczy Christine Skerka Peter F. Zipfel
author_sort	Teresia Hallström
title	CspA from <named-content content-type="genus-species">Borrelia burgdorferi</named-content> Inhibits the Terminal Complement Pathway
title_short	CspA from <named-content content-type="genus-species">Borrelia burgdorferi</named-content> Inhibits the Terminal Complement Pathway
title_full	CspA from <named-content content-type="genus-species">Borrelia burgdorferi</named-content> Inhibits the Terminal Complement Pathway
title_fullStr	CspA from <named-content content-type="genus-species">Borrelia burgdorferi</named-content> Inhibits the Terminal Complement Pathway
title_full_unstemmed	CspA from <named-content content-type="genus-species">Borrelia burgdorferi</named-content> Inhibits the Terminal Complement Pathway
title_sort	cspa from <named-content content-type="genus-species">borrelia burgdorferi</named-content> inhibits the terminal complement pathway
publisher	American Society for Microbiology
publishDate	2013
url	https://doaj.org/article/ab3a9787581841e9812f351fc7ac1be6
work_keys_str_mv	AT teresiahallstrom cspafromnamedcontentcontenttypegenusspeciesborreliaburgdorferinamedcontentinhibitstheterminalcomplementpathway AT corinnasiegel cspafromnamedcontentcontenttypegenusspeciesborreliaburgdorferinamedcontentinhibitstheterminalcomplementpathway AT matthiasmorgelin cspafromnamedcontentcontenttypegenusspeciesborreliaburgdorferinamedcontentinhibitstheterminalcomplementpathway AT peterkraiczy cspafromnamedcontentcontenttypegenusspeciesborreliaburgdorferinamedcontentinhibitstheterminalcomplementpathway AT christineskerka cspafromnamedcontentcontenttypegenusspeciesborreliaburgdorferinamedcontentinhibitstheterminalcomplementpathway AT peterfzipfel cspafromnamedcontentcontenttypegenusspeciesborreliaburgdorferinamedcontentinhibitstheterminalcomplementpathway
_version_	1718427605199224832

CspA from <named-content content-type="genus-species">Borrelia burgdorferi</named-content> Inhibits the Terminal Complement Pathway

Ejemplares similares