Treponema pallidum within cells of a primary chancre from a human female.

Sykes, J.; Miller, James N.; Kalan, A.

doi:10.1136/sti.50.1.40

Cited by 41 publications

(33 citation statements)

References 5 publications

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“…Another possibility is that later during infection a greater number of treponemes reside intracellularly and enter the class I pathway through this route. While T. pallidum is generally considered to be an extracellular pathogen, evidence obtained from microscopic evaluations has suggested that some T. pallidum cells are present inside cells in early lesions (13,25,26). Activated CD8 ϩ T cells within a lesion could contribute to the pool of IFN-␥ available for macrophage activation or could lyse cells containing intracellular treponemes.…”

Section: Discussionmentioning

confidence: 99%

CD4⁺Lymphocytes and Gamma Interferon Predominate in Local Immune Responses in Early Experimental Syphilis

Leader¹,

Godornes

VanVoorhis

et al. 2007

Infect Immun

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The clearance of Treponema pallidum subsp. pallidum from early syphilis lesions involves infiltration of a large number of mononuclear cells and is characteristic of a cell-mediated immune response. In the present study, we sought to determine the relative abundance of different T-lymphocyte populations and Th1/Th2-associated cytokines present in testicular lesions following experimental infection with the Chicago strain of T. pallidum. Using flow cytometry, we examined the proportion of CD4 ؉ and CD8 ؉ T cells present throughout the progression and resolution of primary syphilis in the rabbit model. We related these findings to the results of real-time reverse transcription-PCR quantification of treponemal and cytokine mRNA levels. Treponemal mRNA levels reached peak values on day 18 postinfection, coincident with an initial peak in the level of T cells, which were primarily CD4 ؉ T cells. T-cell levels increased again during resolution of orchitis, and there was an increased proportion of CD8 ؉ T cells. The maximum gamma interferon (IFN-␥) and interleukin-10 (IL-10) mRNA levels were observed on days 11 and 18, respectively, while only negligible amounts of IL-4 and IL-2 were detected throughout the infection. In addition to showing the temporal relationship between treponemal burden and T-cell responses during lesion progression, our results also demonstrate that the composition of the T-cell population changes during lesion resolution. The presence of the mRNA for IFN-␥, but not IL-4, is consistent with cytokine expression in human syphilis and provides further support for the hypothesis that there is a Th1 predominance during the early immune response to T. pallidum.Natural infection with Treponema pallidum subsp. pallidum, the causative agent of syphilis, results in the formation of a primary lesion, or chancre, at the site of infection. A vigorous immune response develops early during infection and results in local clearance of the majority of treponemes and resolution of the primary lesions. The cell phenotypes and cytokines present in early syphilitic lesions during human infection and experimental infection in the rabbit models suggest that the early immune response to T. pallidum is characteristic of a delayedtype hypersensitivity or Th1 response. A large number of mononuclear cells, consisting mostly of T cells and macrophages, infiltrate early lesions prior to bacterial clearance and lesion healing (15,23,24,28). CD4 ϩ helper T cells are believed to mediate bacterial clearance primarily through the production of cytokines, such as gamma interferon (IFN-␥), which activate macrophages (14, 30). Macrophages then engulf and kill opsonized treponemes (2, 17). There is also evidence that activated cytolytic (CD8 ϩ ) T lymphocytes participate in the local immune response within lesions, although their role in clearance remains unclear (18, 31). An important role for antibody in bacterial clearance has also been demonstrated (3, 4, 16); however, reports vary on the relative abundance of B cells within the le...

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Section: Discussionmentioning

confidence: 99%

CD4⁺Lymphocytes and Gamma Interferon Predominate in Local Immune Responses in Early Experimental Syphilis

Leader¹,

Godornes

VanVoorhis

et al. 2007

Infect Immun

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“…Although rare examples of T. pallidum residing within nonphagocytic eukaryotic cells in both tissue culture (46,68) and lesional biopsy specimens from patients (122) have been documented, the spirochete is widely considered to be an extracellular parasite (36,104,113). As such, one might anticipate that the appearance of specific antibodies would herald the eradication of the invader and the control of syphilitic infection, yet as discussed above, clinical and experimental evidence to support this assumption has not been easy to garner.…”

Section: Discussionmentioning

confidence: 99%

Surface Immunolabeling and Consensus Computational Framework To Identify Candidate Rare Outer Membrane Proteins ofTreponema pallidum

Cox

Luthra²,

Dunham-Ems³

et al. 2010

Infect Immun

112

164

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Treponema pallidum reacts poorly with the antibodies present in rabbit and human syphilitic sera, a property attributed to the paucity of proteins in its outer membrane. To better understand the basis for the syphilis spirochete's "stealth pathogenicity," we used a dual-label, 3-step amplified assay in which treponemes encapsulated in gel microdroplets were probed with syphilitic sera in parallel with anti-FlaA antibodies. A small (approximately 5 to 10%) but reproducible fraction of intact treponemes bound IgG and/or IgM antibodies. Three lines of evidence supported the notion that the surface antigens were likely ␤-barrel-forming outer membrane proteins (OMPs): (i) surface labeling with anti-lipoidal (VDRL) antibodies was not observed, (ii) immunoblot analysis confirmed prior results showing that T. pallidum glycolipids are not immunoreactive, and (iii) labeling of intact organisms was not appreciably affected by proteinase K (PK) treatment. With this method, we also demonstrate that TprK (TP0897), an extensively studied candidate OMP, and TP0136, a lipoprotein recently reported to be surface exposed, are both periplasmic. Consistent with the immunolabeling studies, TprK was also found to lack amphiphilicity, a characteristic property of ␤-barrel-forming proteins. Using a consensus computational framework that combined subcellular localization and ␤-barrel structural prediction tools, we generated ranked groups of candidate rare OMPs, the predicted T. pallidum outer membrane proteome (OMPeome), which we postulate includes the surface-exposed molecules detected by our enhanced gel microdroplet assay. In addition to underscoring the syphilis spirochete's remarkably poor surface antigenicity, our findings help to explain the complex and shifting balance between pathogen and host defenses that characterizes syphilitic infection.

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“…Treponemes may be found intracellularly in human and rabbit infections; this possibly protects them from host defence mechanisms and favours their persistence in the face of an immune response (Sykes & Miller, 1971;Sykes et al, 1974;Turk, 1979). However, in early lesions treponemes are predominantly extracellular, often near blood vessels, and clearly accessible to host defences (Drusin et al, 1969;Hasegawa, 1969;Penn, 1981;Penn & Clay, 1982).…”

Section: Introductionmentioning

confidence: 94%

The Outer Membrane of Treponema pallidum: Biological Significance and Biochemical Properties

1985

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Rabbits infected intravenously with Treponema pallidum were not markedly febrile, and the pyrogenicity of treponeme preparations administered intravenously to rabbits was negligible. The antibiotic polymyxin B did not induce any ultrastructural changes on the treponemal surface and was not lethal (immobilizing) for T. pallidum, which was, however, highly susceptible to detergents such as SDS. Extraction of treponemes with Triton X-100 removed the outer membrane (despite the presence of Mg2+) as shown by electron microscopy, and solubilized a limited number of proteins detectable by SDS-PAGE, including a dominant antigen (47 kDal) demonstrated by immunoblotting. None of the proteins were heat-modifiable. Periodic acid-silver staining of polyacrylamide gels for carbohydrate together with protease K digestion did not demonstrate major carbohydrate components in whole treponemes, or in the Triton-soluble fraction. Surface iodination of intact treponemes revealed very little surface exposure of treponemal proteins, although a protein which co-migrated with host albumin was labelled and appeared to be associated with the treponemal surface. Many treponemal proteins were, however, labelled when iodination was done in the presence of Triton. These observations, indicate that the outer membrane of T. pallidum differs significantly from those of many Gram-negative pathogens.

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Treponema pallidum within cells of a primary chancre from a human female.

Cited by 41 publications

References 5 publications

CD4⁺Lymphocytes and Gamma Interferon Predominate in Local Immune Responses in Early Experimental Syphilis

CD4⁺Lymphocytes and Gamma Interferon Predominate in Local Immune Responses in Early Experimental Syphilis

Surface Immunolabeling and Consensus Computational Framework To Identify Candidate Rare Outer Membrane Proteins ofTreponema pallidum

The Outer Membrane of Treponema pallidum: Biological Significance and Biochemical Properties

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Treponema pallidum within cells of a primary chancre from a human female.

Cited by 41 publications

References 5 publications

CD4+Lymphocytes and Gamma Interferon Predominate in Local Immune Responses in Early Experimental Syphilis

CD4+Lymphocytes and Gamma Interferon Predominate in Local Immune Responses in Early Experimental Syphilis

Surface Immunolabeling and Consensus Computational Framework To Identify Candidate Rare Outer Membrane Proteins ofTreponema pallidum

The Outer Membrane of Treponema pallidum: Biological Significance and Biochemical Properties

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CD4⁺Lymphocytes and Gamma Interferon Predominate in Local Immune Responses in Early Experimental Syphilis

CD4⁺Lymphocytes and Gamma Interferon Predominate in Local Immune Responses in Early Experimental Syphilis