Identification of Tp0751 (Pallilysin) as a Treponema pallidum Vascular Adhesin by Heterologous Expression in the Lyme disease Spirochete

Kao, Wei Chien Andrew; Pětrošová, Helena; Ebady, Rhodaba; Lithgow, Karen V.; Rojas, Pablo-David; Zhang, Yang; Kim, Yae Eun; Kim, Yae Ram; Odisho, Tanya; Gupta, Nupur; Moter, Annette; Cameron, Caroline E.; Moriarty, Tara J.

doi:10.1038/s41598-017-01589-4

Cited by 30 publications

(45 citation statements)

References 66 publications

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“…Further, we show attachment of Tp0751 to the immortalized blood-brain barrier model cell line hCMEC/d3, an important first step in investigating the contribution of this adhesin to the process of T. pallidum neuroinvasion. Taken in the context of our previous findings, which demonstrate that Tp0751 functions as a vascular adhesin in vitro and in vivo when expressed heterologously in a model spirochete (45,48), these results present evidence using three distinct approaches that Tp0751 is an endothelial adhesin.…”

Section: Discussionsupporting

confidence: 80%

“…Endothelial interactions are mediated by the C-terminal lipocalin foldcontaining domain of Tp0751. With the knowledge that Tp0751 can function as a vascular adhesin when expressed in a heterologous system (45,48), we sought to further characterize endothelial interactions mediated by this T. pallidum protein. To delineate the endothelial binding interface of Tp0751, recombinant protein attachment to endothelial monolayers was evaluated using constructs with various N-terminal truncations.…”

Section: Resultsmentioning

confidence: 99%

“…However, the true reason for the discrepancy is currently unknown, and since the proteolytic and adhesive activities of Tp0751 have been shown to function independently (47), we focused subsequent investigations on characterizing the adhesive functions of Tp0751. These studies have shown that heterologous expression of Tp0751 in a noninfectious Borrelia burgdorferi model system confers a gain-of-function phenotype for endothelial attachment in vitro and in vivo (45,48). Further, biochemical investigations with Tp0751 peptides demonstrated that one face of the lipocalin fold and N-terminal helix confer binding to ECM components, whereas competitive inhibition studies with Tp0751-expressing B. burgdorferi demon-strated that binding to endothelial cells was confined to a discrete region within the lipocalin fold (45).…”

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confidence: 99%

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Identification of the Neuroinvasive Pathogen Host Target, LamR, as an Endothelial Receptor for the Treponema pallidum Adhesin Tp0751

Lithgow

Church

Gomez

et al. 2020

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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.

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Section: Discussionsupporting

confidence: 80%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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Identification of the Neuroinvasive Pathogen Host Target, LamR, as an Endothelial Receptor for the Treponema pallidum Adhesin Tp0751

Lithgow

Church

Gomez

et al. 2020

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“…Возможными мишенями для вакцин против сифилиса являются отдельные подгруппы белков, относящихся к семейству Tpr (T. pallidum repeat) (нацеливание на восприимчивость к инфекции и персистирование возбудителя), и белок Tp0751 (трепонемный белок паллилизин, относящийся к адгезинам) (нацеливание на распространение возбудителя) [8,10]. Новым подходом к созданию вакцины было использование инактивированной Borrelia burgdorferi в качестве эффективного носителя для доставки антигенов и индукции специфического ответа макроорганизма на антигены T. pallidum, экспрессируемые генами tp0897 (tprK) и tp0435 [11].…”

Section: сифилисunclassified

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2019

CMAC

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“…Endothelial dysfunction plays key roles in vascular intimal inflammation by initiating the formation of atherosclerotic plaques and thrombosis [12]. It is also the key step of systemic dissemination and pathophysiological basic of syphilis [13-14]. We investigated the effect of Tp0965 as well as Tp17 on endothelial cells.…”

Section: Introductionmentioning

confidence: 99%

Chemerin Induced byTreponema pallidumPredicted Membrane Protein Tp0965 Mediates Endothelial Dysfunction via Activating MAPK Signaling Pathway

Zhang

Yang

Wang

2018

Preprint

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24Chemerin, a chemoattractant protein, is involved in endothelial dysfunction and 25 vascular inflammation in pathological conditions. In a recent study, we observed the 26 upregulation of chemerin in endothelial cells following in vitro treatment with T. 27 pallidum. Here, we investigated the role of chemerin in endothelial cells dysfunction 28 induced by the T. pallidum predicted membrane protein Tp0965. Following 29 stimulation of human umbilical vein endothelial cells (HUVECs) with Tp0965, 30 chemerin and its ChemR23 receptor were up-regulated, companied with elevated 31 expression of TLR2. Furthermore, chemerin from HUVECs activated endothelial cells 32 via chemerin/ChemR23 signaling in an autocrine/paracrine manner, characterized by 33 upregulated expression of ICAM-1, E-selectin and MMP-2. Activation of endothelial 34 cells depended on the MAPK signaling pathway. In addition, Tp0965-induced 35 chemerin promoted monocytes migration to endothelial cells, also via 36 chemerin/ChemR23 pathway. The RhoA/ROCK signaling pathway was also involved 37 in monocytes migration in response to chemerin/ChemR23. Our results highlight the 38 role of Tp0965-induced chemerin in endothelial cells dysfunction, which contributes to 39 the immunopathogenesis of vascular inflammation of syphilis.40 Author summary 41 Treponema pallidum is the spirochete of syphilis, which causes a chronic system 42 inflammation. Endothelium damage caused by this bacterium is the key step in the 43 systemic dissemination and pathophysiology of syphilis, particularly cardiovascular 44 syphilis and neurosyphilis. In this study, we show a novel molecular mechanism of 3 45 endothelium damage induce by Treponema pallidum predicted membrane protein 46 Tp0965. Chemerin is a recently identified adipocytokine and chemoattractant protein 47 with a crucial role in endothelial dysfunction and vascular inflammation in pathological 48 conditions. Our data show that Tp0965 up-regulated the expression of chemerin and its 49 ChemR23 receptor by endothelial cells in vitro. Furthermore, chemerin from HUVECs 50 activated endothelial cells via chemerin/ChemR23 signaling in an autocrine/paracrine 51 manner and depended on the MAPK signaling pathway. In addition, Tp0965-induced 52 chemerin promoted monocytes migration to endothelial cells, also via 53 chemerin/ChemR23 pathway. The RhoA/ROCK signaling pathway was also involved 54 in monocytes migration in response to chemerin/ChemR23. These findings contribute 55 to the immunopathogenesis of vascular inflammation of syphilis. 56 57 Introduction 58 Treponema pallidum subsp. pallidum (T. pallidum) is the spirochete of syphilis, a 59 sexually transmitted infection that remains an important public health problem around 60 the world [1]. Infection by this bacterium causes a chronic system inflammation, and if 61 untreated can seriously and irreversibly damage the nervous and cardiovascular system.62 Cardiovascular syphilis is associated with multiple clinical syndromes, of which aortic 63 aneurysms, aortic insufficiency,...

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Identification of Tp0751 (Pallilysin) as a Treponema pallidum Vascular Adhesin by Heterologous Expression in the Lyme disease Spirochete

Cited by 30 publications

References 66 publications

Identification of the Neuroinvasive Pathogen Host Target, LamR, as an Endothelial Receptor for the Treponema pallidum Adhesin Tp0751

Identification of the Neuroinvasive Pathogen Host Target, LamR, as an Endothelial Receptor for the Treponema pallidum Adhesin Tp0751

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Chemerin Induced byTreponema pallidumPredicted Membrane Protein Tp0965 Mediates Endothelial Dysfunction via Activating MAPK Signaling Pathway

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