Treponema pallidum Disrupts VE-Cadherin Intercellular Junctions and Traverses Endothelial Barriers Using a Cholesterol-Dependent Mechanism

Lithgow, Karen V.; Tsao, Emily; Schovanek, Ethan; Gomez, Alloysius; Swayne, Leigh Anne; Cameron, Caroline E.

doi:10.3389/fmicb.2021.691731

Cited by 21 publications

(18 citation statements)

References 73 publications

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“…The optimized workflow reported in this study detected, for the first time, expression of 11 OMPs from T. pallidum grown under infection conditions (in vivo-grown T. pallidum ). Literature reports provide evidence that several of these detected proteins play key roles in T. pallidum pathogenesis and have been identified as current syphilis vaccine candidates, including TPANIC_0751 51 , 63 , 64 , TPANIC_0897 (TprK) 16 , 65 , 66 , and TPANIC_1031 (TprL) 48 . Most of the detected Tpr proteins are predicted to be surface-exposed OMPs and have been shown to elicit an immune response during experimental syphilis infection 67 – 69 .…”

Section: Discussionmentioning

confidence: 99%

Deep proteome coverage advances knowledge of Treponema pallidum protein expression profiles during infection

Houston,

Gomez,

Geppert

et al. 2023

Sci Rep

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Comprehensive proteome-wide analysis of the syphilis spirochete, Treponema pallidum ssp. pallidum, is technically challenging due to high sample complexity, difficulties with obtaining sufficient quantities of bacteria for analysis, and the inherent fragility of the T. pallidum cell envelope which further complicates proteomic identification of rare T. pallidum outer membrane proteins (OMPs). The main aim of the present study was to gain a deeper understanding of the T. pallidum global proteome expression profile under infection conditions. This will corroborate and extend genome annotations, identify protein modifications that are unable to be predicted at the genomic or transcriptomic levels, and provide a foundational knowledge of the T. pallidum protein expression repertoire. Here we describe the optimization of a T. pallidum-specific sample preparation workflow and mass spectrometry-based proteomics pipeline which allowed for the detection of 77% of the T. pallidum protein repertoire under infection conditions. When combined with prior studies, this brings the overall coverage of the T. pallidum proteome to almost 90%. These investigations identified 27 known/predicted OMPs, including potential vaccine candidates, and detected expression of 11 potential OMPs under infection conditions for the first time. The optimized pipeline provides a robust and reproducible workflow for investigating T. pallidum protein expression during infection. Importantly, the combined results provide the deepest coverage of the T. pallidum proteome to date.

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Section: Discussionmentioning

confidence: 99%

Deep proteome coverage advances knowledge of Treponema pallidum protein expression profiles during infection

Houston,

Gomez,

Geppert

et al. 2023

Sci Rep

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“…Quantification of RNA was done by targeting both the proposed PBP gene, tp47 , and a flagellar sheath protein, flaA . Both primer sets were constructed by Integrated DNA Technologies and have been previously validated elsewhere 17 , 86 .…”

Section: Methodsmentioning

confidence: 99%

A large screen identifies beta-lactam antibiotics which can be repurposed to target the syphilis agent

Hayes

Dressler

Norris

et al. 2023

npj Antimicrob Resist

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Syphilis, caused by the spirochete Treponema pallidum subsp. pallidum (hereafter called T. pallidum), is re-emerging as a worldwide sexually transmitted infection. A single intramuscular dose of benzathine penicillin G is the preferred syphilis treatment option. Both supply shortage concerns and the potential for acquired antibiotic resistance further the need to broaden the repertoire of syphilis therapeutics. We reasoned that other β-lactams may be equally or more effective at targeting the disease-causing agent, Treponema pallidum, but have yet to be discovered due to a previous lack of a continuous in vitro culture system. Recent technical advances with respect to in vitro T. pallidum propagation allowed us to conduct a high-throughput screen of almost 100 β-lactams. Using several molecular and cellular approaches that we developed or adapted, we identified and confirmed the efficacy of several β-lactams that were similar to or outperformed the current standard, benzathine penicillin G. These options are either currently used to treat bacterial infections or are synthetic derivatives of naturally occurring compounds. Our studies not only identified additional potential therapeutics in the resolution of syphilis, but provide techniques to study the complex biology of T. pallidum—a spirochete that has plagued human health for centuries.

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“…Similarly, recombinant TP0965 shows a higher level of endothelial permeability induction ( 39 ). Both intercellular junction pathways and lipid raft-mediated endocytosis mechanisms for traversing endothelial barriers were observed in T. pallidum , but without disruption of barrier permeability ( 35 ). The latter view seems more reliable due to the normal or only slightly increased quotient (Q alb ) level in neurosyphilis patients in clinical practice ( 40 ).…”

Section: The Mechanisms Of Invasion Of the Cns By T Pallidummentioning

confidence: 99%

“…( B) Several T. pallidum proteins are identified to be adhesins, including laminin- (TP0751) and fibronectin- (TP0136, TP0155, TP0483) binding proteins ( 34 ). ( C) T. pallidum adheres to endothelial cells at the site of intercellular junction, resulting in a notable reduction in the expression of tight junction proteins ZO-1 and occludin through TP0751, and disrupting VE-cadherin, thereby entering the BBB through a paracellular pathway; TP0751 coordinates intercellular transport by engaging with host receptors (LamR) in lipid rafts and inducing endothelial uptake and transport in a cholesterol-dependent manner ( 35 ). The figure was created in BioRender.…”

Section: The Mechanisms Of Invasion Of the Cns By T Pallidummentioning

confidence: 99%

Neurosyphilis: insights into its pathogenesis, susceptibility, diagnosis, treatment, and prevention

Wu,

Ye,

Wang

et al. 2024

Front. Neurol.

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Background and aimInvasion of the central nervous system by Treponema pallidum can occur at any stage of syphilis. In the event that T. pallidum is not cleared promptly, certain individuals may experience progression to neurosyphilis, which manifests as cognitive and behavioral abnormalities, limb paralysis, and potentially fatal outcomes. Early identification or prevention of neurosyphilis is therefore crucial. The aim of this paper is to conduct a critical and narrative review of the latest information focusing exclusively to the pathogenesis and clinical management of neurosyphilis.MethodologyTo compile this review, we have conducted electronic literature searches from the PubMed database relating to neurosyphilis. Priority was given to studies published from the past 10 years (from 2013 to 2023) and other studies if they were of significant importance (from 1985 to 2012), including whole genome sequencing results, cell structure of T. pallidum, history of genotyping, and other related topics. These studies are classic or reflect a developmental process.ResultsNeurosyphilis has garnered global attention, yet susceptibility to and the pathogenesis of this condition remain under investigation. Cerebrospinal fluid examination plays an important role in the diagnosis of neurosyphilis, but lacks the gold standard. Intravenous aqueous crystalline penicillin G continues to be the recommended therapeutic approach for neurosyphilis. Considering its sustained prominence, it is imperative to develop novel public health tactics in order to manage the resurgence of neurosyphilis.ConclusionThis review gives an updated narrative description of neurosyphilis with special emphasis on its pathogenesis, susceptibility, diagnosis, treatment, and prevention.

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Treponema pallidum Disrupts VE-Cadherin Intercellular Junctions and Traverses Endothelial Barriers Using a Cholesterol-Dependent Mechanism

Cited by 21 publications

References 73 publications

Deep proteome coverage advances knowledge of Treponema pallidum protein expression profiles during infection

Deep proteome coverage advances knowledge of Treponema pallidum protein expression profiles during infection

A large screen identifies beta-lactam antibiotics which can be repurposed to target the syphilis agent

Neurosyphilis: insights into its pathogenesis, susceptibility, diagnosis, treatment, and prevention

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