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

Download Full-text

Treponema pallidum pallidum Genotypes and Macrolide Resistance Status in Syphilitic Lesions among Patients at 2 Sexually Transmitted Infection Clinics in Lima, Peru

Sexually Transmitted Diseases ◽

10.1097/01.olq.0000508403.16282.69 ◽

2016 ◽

Vol 43 (12) ◽

pp. 781

Keyword(s):

Sexually Transmitted Infection ◽

Treponema Pallidum ◽

Macrolide Resistance ◽

Transmitted Infection ◽

Sexually Transmitted

Download Full-text

Expansion of Comprehensive Screening of Male Sexually Transmitted Infection Clinic Attendees with Mycoplasma genitalium and Trichomonas vaginalis Molecular Assessment: a Retrospective Analysis

Journal of Clinical Microbiology ◽

10.1128/jcm.01625-16 ◽

2016 ◽

Vol 55 (1) ◽

pp. 321-325 ◽

Cited By ~ 10

Author(s):

Erik Munson ◽

David Wenten ◽

Sheila Jhansale ◽

Mary Kay Schuknecht ◽

Nicki Pantuso ◽

...

Keyword(s):

Sexually Transmitted Infection ◽

Trichomonas Vaginalis ◽

Screening Program ◽

Mycoplasma Genitalium ◽

Transmitted Infection ◽

Additional Specimen ◽

Content Type ◽

Sexually Transmitted ◽

High Prevalence ◽

Infection Clinic

ABSTRACTOf 1,493 encounters of males at a sexually transmitted infection (STI) clinic in a community with a high prevalence of STI,Chlamydia trachomatiswas detected in 8.7% andNeisseria gonorrhoeaewas detected in 6.6%. AdditionalTrichomonas vaginalisandMycoplasma genitaliumscreening found 17.4% and 23.9% of the encounters, respectively, to be positive for STI. STI agents were detected in 13.7% of urine specimens; addition of pharyngeal and rectal collections to the analysis resulted in detection of STI agents in 19.0% and 23.9% of encounters, respectively. A total of 101 (23.8%) encounters of identified STI involved sole detection ofM. genitalium. Expansion of the STI analyte panel (includingM. genitalium) and additional specimen source sampling within a comprehensive STI screening program increase identification of male STI carriers.

Download Full-text

Genomic epidemiology of syphilis reveals independent emergence of macrolide resistance across multiple circulating lineages

10.1101/413161 ◽

2018 ◽

Author(s):

Mathew A. Beale ◽

Michael Marks ◽

Sharon K. Sahi ◽

Lauren C. Tantalo ◽

Achyuta V. Nori ◽

...

Keyword(s):

Antimicrobial Resistance ◽

Sexually Transmitted Infection ◽

Direct Sequencing ◽

Treponema Pallidum ◽

Macrolide Resistance ◽

Transmitted Infection ◽

Sexually Transmitted ◽

Genomic Epidemiology ◽

Phylogenomic Analyses

AbstractSyphilis is a sexually transmitted infection caused byTreponema pallidumsubspeciespallidumand may lead to severe complications. Recent years have seen striking increases in syphilis in many countries. Previous analyses have suggested one lineage of syphilis, SS14, may have expanded recently, indicating emergence of a single pandemic azithromycin-resistant cluster. We used direct sequencing ofT. pallidumcombined with phylogenomic analyses to show that both SS14- and Nichols-lineages are simultaneously circulating in clinically relevant populations in multiple countries. We correlate the appearance of genotypic macrolide resistance with multiple independently evolved SS14 sub-lineages and show that genotypically resistant and sensitive sub-lineages are spreading contemporaneously, incompatible with the notion that SS14-lineage expansion is driven purely by macrolide resistance. These findings inform our understanding of the current syphilis epidemic by demonstrating how macrolide resistance evolves inTreponemasubspecies and provide a warning on broader issues of antimicrobial resistance.

Download Full-text

Syphilis

Oxford Handbook of Genitourinary Medicine, HIV, and Sexual Health ◽

10.1093/med/9780198783497.003.0007 ◽

2019 ◽

pp. 117-136

Keyword(s):

Side Effects ◽

20Th Century ◽

Sexually Transmitted Infection ◽

Partner Notification ◽

Treponema Pallidum ◽

Transmitted Infection ◽

Sexually Transmitted ◽

Treatment Side Effects ◽

Management Of Complications ◽

Women And Children

Treponema pallidum is the bacterial spirochaete responsible for the sexually transmitted infection syphilis. Syphilis has been recognized as an STI since at least the mid-1500s. Rates declined in the second half of the 20th century, but in the past 20 years have risen >20-fold with >4000 cases per year since 2014. This chapter discusses epidemiology, clinical features of the different stages of syphilis, and management of adults, pregnant women, and children diagnosed with syphilis. The management of complications of syphilis are also explained, including neurosyphilis. Treatment side effects, partner notification, and epidemiological treatment is also covered

Download Full-text

Challenges and Controversies Concerning Neisseria gonorrhoeae-Neutrophil Interactions in Pathogenesis

mBio ◽

10.1128/mbio.00721-21 ◽

2021 ◽

Author(s):

Alison K. Criss ◽

Caroline A. Genco ◽

Scott D. Gray-Owen ◽

Ann E. Jerse ◽

H Steven Seifert

Keyword(s):

Neisseria Gonorrhoeae ◽

Sexually Transmitted Infection ◽

Infection Rates ◽

Transmitted Infection ◽

Content Type ◽

Sexually Transmitted

The bacterium Neisseria gonorrhoeae (Ngo) is the main cause of the sexually transmitted infection gonorrhea. The global incidence of 87 million new Ngo infections each year, rising infection rates, and the emergence of Ngo strains that are resistant to all clinically recommended antibiotics have raised the specter of untreatable infections (M.

Download Full-text

The Gonococcal NlpD Protein Facilitates Cell Separation by Activating Peptidoglycan Cleavage by AmiC

Journal of Bacteriology ◽

10.1128/jb.00540-15 ◽

2015 ◽

Vol 198 (4) ◽

pp. 615-622 ◽

Cited By ~ 9

Author(s):

Elizabeth A. Stohl ◽

Jonathan D. Lenz ◽

Joseph P. Dillard ◽

H. Steven Seifert

Keyword(s):

Cell Division ◽

Causative Agent ◽

Sexually Transmitted Infection ◽

Cell Separation ◽

Pathogenic Bacteria ◽

Transmitted Infection ◽

Poor Growth ◽

Gram Negative ◽

Content Type ◽

Sexually Transmitted

ABSTRACTKey steps in bacterial cell division are the synthesis and subsequent hydrolysis of septal peptidoglycan (PG), which allow efficient separation of daughter cells. Extensive studies in the Gram-negative, rod-shaped bacteriumEscherichia colihave revealed that this hydrolysis is highly regulated spatially and temporally.Neisseria gonorrhoeaeis an obligate Gram-negative, diplococcal pathogen and is the only causative agent of the sexually transmitted infection gonorrhea. We investigated how cell separation proceeds in this diplococcal organism. We demonstrated that deletion of thenlpDgene in strain FA1090 leads to poor growth and to an altered colony and cell morphology. An isopropyl-beta-d-galactopyranoside (IPTG)-regulatednlpDcomplemented construct can restore these defects only when IPTG is supplied in the growth medium. Thin-section transmission electron microscopy (TEM) revealed that thenlpDmutant strain grew in large clumps containing live and dead bacteria, which was consistent with deficient cell separation. Biochemical analyses of purified NlpD protein showed that it was able to bind purified PG. Finally, we showed that, although NlpD has no hydrolase activity itself, NlpD potentiates the hydrolytic activity of AmiC. These results indicate thatN. gonorrhoeaeNlpD is required for proper cell growth and division through its interactions with the amidase AmiC.IMPORTANCEN. gonorrhoeaeis the sole causative agent of the sexually transmitted infection gonorrhea. The incidence of antibiotic-resistant gonococcal infections has risen sharply in recent years, andN. gonorrhoeaehas been classified as a “superbug” by the CDC. Since there is a dearth of new antibiotics to combat gonococcal infections, elucidating the essential cellular process ofN. gonorrhoeaemay point to new targets for antimicrobial therapies. Cell division and separation is one such essential process. We identified and characterized the gonococcalnlpDgene and showed that it is essential for cell separation. In contrast to other pathogenic bacteria, the gonococcal system is streamlined and does not appear to have any redundancies.

Download Full-text

Antibiotic Use before Chlamydia and Gonorrhea Genital and Extragenital Screening in the Sexually Transmitted Infection Clinical Setting

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.03932-14 ◽

2014 ◽

Vol 59 (1) ◽

pp. 121-128 ◽

Cited By ~ 6

Author(s):

Nicole H. T. M. Dukers-Muijrers ◽

Genevieve A. F. S. van Liere ◽

Petra F. G. Wolffs ◽

Casper Den Heijer ◽

Marita I. L. S. Werner ◽

...

Keyword(s):

Sexually Transmitted Infection ◽

Clinical Setting ◽

Antibiotic Use ◽

Antibiotic Consumption ◽

Heterosexual Men ◽

Transmitted Infection ◽

Content Type ◽

Sexually Transmitted ◽

Sex With Men ◽

Test Result

ABSTRACTBackground antibiotic use (i.e., administration of antibiotics not directly related toChlamydia trachomatisorNeisseria gonorrhoeaeinfections) has been associated with a lower prevalence of genitalC. trachomatisinfection in a clinical setting. Associations with specific antibiotic types or withN. gonorrhoeaeare lacking. Here, we assessed the prevalence of antibiotic use, the different classes and agents used, and their association with a subsequent sexually transmitted infection (STI) clinicC. trachomatisandN. gonorrhoeaetest result. At our STI clinic, we systematically registered whether antibiotics were used in the past month (in 29% of the cases, the specific antibiotic agent was named). Patients were screened for urogenitalC. trachomatisandN. gonorrhoeae; a third of them were also screened for anorectal and oropharyngealC. trachomatisandN. gonorrhoeae. The proportion of antibiotics used and their association withC. trachomatisandN. gonorrhoeaeprevalence were assessed for heterosexual men, men who have sex with men (MSM), and women. During 14,775 clinic consultations, antibiotic use was reported by 12.2% (95% confidence interval [CI], 11.7% to 12.7%), i.e., 14.8% of women, 8.6% of heterosexual men, and 11.6% of MSM. The most reported antibiotics were penicillins, tetracyclines, and macrolides, respectively. The prevalence was 11.0% (95% CI, 10.3% to 11.3%) forC. trachomatisand 1.9% (95% CI, 1.7% to 2.1%) forN. gonorrhoeae. Only tetracycline use was associated with a lowerC. trachomatisprevalence (3%). Overall antibiotic use was associated with lower anorectalC. trachomatisprevalence in MSM only (odds ratio, 0.4; 95% CI, 0.2 to 0.8). STI clinic visitors commonly report recent antibiotic use. Even in a country with low antibiotic consumption, tetracycline use impactedC. trachomatisprevalence, while there was a notable absence of association with azithromycin.

Download Full-text

Rare Case of Four Osseous Lesions of the Skull in a Patient with Secondary Syphilis

Case Reports in Infectious Diseases ◽

10.1155/2018/3148758 ◽

2018 ◽

Vol 2018 ◽

pp. 1-3 ◽

Cited By ~ 1

Author(s):

Jace Kusler ◽

Supha Arthurs

Keyword(s):

Sexually Transmitted Infection ◽

Rare Case ◽

Congenital Syphilis ◽

Treponema Pallidum ◽

Secondary Syphilis ◽

Bone Involvement ◽

Transmitted Infection ◽

Sexually Transmitted ◽

Organ Systems ◽

Rare Manifestation

Syphilis is a sexually transmitted infection that is caused by the bacterium Treponema pallidum. Syphilis can present as primary, secondary, tertiary, or congenital. It can have an effect on many different organ systems and tissues leading to a wide variety of symptoms and complications; one rare manifestation is bone involvement. The patient in this case was diagnosed with secondary and early neurosyphilis and was also found to have skull lesions that were due to Treponema pallidum. There are guidelines for the treatment of primary, secondary, tertiary, and congenital syphilis; however, there are currently no guidelines for the treatment of syphilis with bone involvement.

Download Full-text

Conservation of the Host-Interacting Proteins Tp0750 and Pallilysin among Treponemes and Restriction of Proteolytic Capacity to Treponema pallidum

Infection and Immunity ◽

10.1128/iai.00643-15 ◽

2015 ◽

Vol 83 (11) ◽

pp. 4204-4216 ◽

Cited By ~ 7

Author(s):

Simon Houston ◽

John S. Taylor ◽

Yavor Denchev ◽

Rebecca Hof ◽

Richard L. Zuerner ◽

...

Keyword(s):

Sequence Similarity ◽

Membrane Integrity ◽

Treponema Pallidum ◽

Host Protein ◽

Host Proteins ◽

Transmitted Infection ◽

Content Type ◽

Sexually Transmitted ◽

Less Invasive

ABSTRACTThe spirocheteTreponema pallidumsubsp.pallidumis the causative agent of syphilis, a chronic, sexually transmitted infection characterized by multiple symptomatic and asymptomatic stages. Although several other species in the genus are able to cause or contribute to disease,T. pallidumdiffers in that it is able to rapidly disseminate via the bloodstream to tissue sites distant from the site of initial infection. It is also the onlyTreponemaspecies able to cross both the blood-brain and placental barriers. Previously, theT. pallidumproteins, Tp0750 and Tp0751 (also called pallilysin), were shown to degrade host proteins central to blood coagulation and basement membrane integrity, suggesting a role for these proteins inT. pallidumdissemination and tissue invasion. In the present study, we characterized Tp0750 and Tp0751 sequence variation in a diversity of pathogenic and nonpathogenic treponemes. We also determined the proteolytic potential of the orthologs from the less invasive speciesTreponema denticolaandTreponema phagedenis. These analyses showed high levels of sequence similarity among Tp0750 orthologs from pathogenic species. For pallilysin, lower levels of sequence conservation were observed between this protein and orthologs from other treponemes, except for the ortholog from the highly invasive rabbit venereal syphilis-causingTreponema paraluiscuniculi.In vitrohost component binding and degradation assays demonstrated that pallilysin and Tp0750 orthologs from the less invasive treponemes tested were not capable of binding or degrading host proteins. The results show that pallilysin and Tp0750 host protein binding and degradative capability is positively correlated with treponemal invasiveness.

Download Full-text