Identification of the Neuroinvasive Pathogen Host Target, LamR, as an Endothelial Receptor for the <named-content content-type="genus-species">Treponema pallidum</named-content> Adhesin Tp0751

ABSTRACT Treponema pallidum subsp. pallidum is the causative agent of syphilis, a human-specific sexually transmitted infection that causes a multistage disease with diverse clinical manifestations. Treponema pallidum undergoes rapid vascular dissemination to penetrate tissue, placental, and blood-b...

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Autores principales:	Karen V. Lithgow, Brigette Church, Alloysius Gomez, Emily Tsao, Simon Houston, Leigh Anne Swayne, Caroline E. Cameron
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	adhesin endothelial cells invasive bacteria laminin receptor syphilis Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/57571949b48c4a86af8ec569bcdf5b56
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spelling	oai:doaj.org-article:57571949b48c4a86af8ec569bcdf5b562021-11-15T15:29:17ZIdentification of the Neuroinvasive Pathogen Host Target, LamR, as an Endothelial Receptor for the <named-content content-type="genus-species">Treponema pallidum</named-content> Adhesin Tp075110.1128/mSphere.00195-202379-5042https://doaj.org/article/57571949b48c4a86af8ec569bcdf5b562020-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00195-20https://doaj.org/toc/2379-5042ABSTRACT Treponema pallidum subsp. pallidum is the causative agent of syphilis, a human-specific sexually transmitted infection that causes a multistage disease with diverse clinical manifestations. Treponema pallidum undergoes rapid vascular dissemination to penetrate tissue, placental, and blood-brain barriers and gain access to distant tissue sites. The rapidity and extent of T. pallidum dissemination are well documented, but the molecular mechanisms have yet to be fully elucidated. One protein that has been shown to play a role in treponemal dissemination is Tp0751, a T. pallidum adhesin that interacts with host components found within the vasculature and mediates bacterial adherence to endothelial cells under shear flow conditions. In this study, we further explore the molecular interactions of Tp0751-mediated adhesion to the vascular endothelium. We demonstrate that recombinant Tp0751 adheres to human endothelial cells of macrovascular and microvascular origin, including a cerebral brain microvascular endothelial cell line. Adhesion assays using recombinant Tp0751 N-terminal truncations reveal that endothelial binding is localized to the lipocalin fold-containing domain of the protein. We also confirm this interaction using live T. pallidum and show that spirochete attachment to endothelial monolayers is disrupted by Tp0751-specific antiserum. Further, we identify the 67-kDa laminin receptor (LamR) as an endothelial receptor for Tp0751 using affinity chromatography, coimmunoprecipitation, and plate-based binding methodologies. Notably, LamR has been identified as a receptor for adhesion of other neurotropic invasive bacterial pathogens to brain endothelial cells, including Neisseria meningitidis, Haemophilus influenzae, and Streptococcus pneumoniae, suggesting the existence of a common mechanism for extravasation of invasive extracellular bacterial pathogens. IMPORTANCE Syphilis is a sexually transmitted infection caused by the spirochete bacterium Treponema pallidum subsp. pallidum. The continued incidence of syphilis demonstrates that screening and treatment strategies are not sufficient to curb this infectious disease, and there is currently no vaccine available. Herein we demonstrate that the T. pallidum adhesin Tp0751 interacts with endothelial cells that line the lumen of human blood vessels through the 67-kDa laminin receptor (LamR). Importantly, LamR is also a receptor for meningitis-causing neuroinvasive bacterial pathogens such as Neisseria meningitidis, Haemophilus influenzae, and Streptococcus pneumoniae. Our findings enhance understanding of the Tp0751 adhesin and present the intriguing possibility that the molecular events of Tp0751-mediated treponemal dissemination may mimic the endothelial interaction strategies of other invasive pathogens.Karen V. LithgowBrigette ChurchAlloysius GomezEmily TsaoSimon HoustonLeigh Anne SwayneCaroline E. CameronAmerican Society for Microbiologyarticleadhesinendothelial cellsinvasive bacterialaminin receptorsyphilisMicrobiologyQR1-502ENmSphere, Vol 5, Iss 2 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	adhesin endothelial cells invasive bacteria laminin receptor syphilis Microbiology QR1-502
spellingShingle	adhesin endothelial cells invasive bacteria laminin receptor syphilis Microbiology QR1-502 Karen V. Lithgow Brigette Church Alloysius Gomez Emily Tsao Simon Houston Leigh Anne Swayne Caroline E. Cameron Identification of the Neuroinvasive Pathogen Host Target, LamR, as an Endothelial Receptor for the <named-content content-type="genus-species">Treponema pallidum</named-content> Adhesin Tp0751
description	ABSTRACT Treponema pallidum subsp. pallidum is the causative agent of syphilis, a human-specific sexually transmitted infection that causes a multistage disease with diverse clinical manifestations. Treponema pallidum undergoes rapid vascular dissemination to penetrate tissue, placental, and blood-brain barriers and gain access to distant tissue sites. The rapidity and extent of T. pallidum dissemination are well documented, but the molecular mechanisms have yet to be fully elucidated. One protein that has been shown to play a role in treponemal dissemination is Tp0751, a T. pallidum adhesin that interacts with host components found within the vasculature and mediates bacterial adherence to endothelial cells under shear flow conditions. In this study, we further explore the molecular interactions of Tp0751-mediated adhesion to the vascular endothelium. We demonstrate that recombinant Tp0751 adheres to human endothelial cells of macrovascular and microvascular origin, including a cerebral brain microvascular endothelial cell line. Adhesion assays using recombinant Tp0751 N-terminal truncations reveal that endothelial binding is localized to the lipocalin fold-containing domain of the protein. We also confirm this interaction using live T. pallidum and show that spirochete attachment to endothelial monolayers is disrupted by Tp0751-specific antiserum. Further, we identify the 67-kDa laminin receptor (LamR) as an endothelial receptor for Tp0751 using affinity chromatography, coimmunoprecipitation, and plate-based binding methodologies. Notably, LamR has been identified as a receptor for adhesion of other neurotropic invasive bacterial pathogens to brain endothelial cells, including Neisseria meningitidis, Haemophilus influenzae, and Streptococcus pneumoniae, suggesting the existence of a common mechanism for extravasation of invasive extracellular bacterial pathogens. IMPORTANCE Syphilis is a sexually transmitted infection caused by the spirochete bacterium Treponema pallidum subsp. pallidum. The continued incidence of syphilis demonstrates that screening and treatment strategies are not sufficient to curb this infectious disease, and there is currently no vaccine available. Herein we demonstrate that the T. pallidum adhesin Tp0751 interacts with endothelial cells that line the lumen of human blood vessels through the 67-kDa laminin receptor (LamR). Importantly, LamR is also a receptor for meningitis-causing neuroinvasive bacterial pathogens such as Neisseria meningitidis, Haemophilus influenzae, and Streptococcus pneumoniae. Our findings enhance understanding of the Tp0751 adhesin and present the intriguing possibility that the molecular events of Tp0751-mediated treponemal dissemination may mimic the endothelial interaction strategies of other invasive pathogens.
format	article
author	Karen V. Lithgow Brigette Church Alloysius Gomez Emily Tsao Simon Houston Leigh Anne Swayne Caroline E. Cameron
author_facet	Karen V. Lithgow Brigette Church Alloysius Gomez Emily Tsao Simon Houston Leigh Anne Swayne Caroline E. Cameron
author_sort	Karen V. Lithgow
title	Identification of the Neuroinvasive Pathogen Host Target, LamR, as an Endothelial Receptor for the <named-content content-type="genus-species">Treponema pallidum</named-content> Adhesin Tp0751
title_short	Identification of the Neuroinvasive Pathogen Host Target, LamR, as an Endothelial Receptor for the <named-content content-type="genus-species">Treponema pallidum</named-content> Adhesin Tp0751
title_full	Identification of the Neuroinvasive Pathogen Host Target, LamR, as an Endothelial Receptor for the <named-content content-type="genus-species">Treponema pallidum</named-content> Adhesin Tp0751
title_fullStr	Identification of the Neuroinvasive Pathogen Host Target, LamR, as an Endothelial Receptor for the <named-content content-type="genus-species">Treponema pallidum</named-content> Adhesin Tp0751
title_full_unstemmed	Identification of the Neuroinvasive Pathogen Host Target, LamR, as an Endothelial Receptor for the <named-content content-type="genus-species">Treponema pallidum</named-content> Adhesin Tp0751
title_sort	identification of the neuroinvasive pathogen host target, lamr, as an endothelial receptor for the <named-content content-type="genus-species">treponema pallidum</named-content> adhesin tp0751
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/57571949b48c4a86af8ec569bcdf5b56
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Identification of the Neuroinvasive Pathogen Host Target, LamR, as an Endothelial Receptor for the <named-content content-type="genus-species">Treponema pallidum</named-content> Adhesin Tp0751

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