Segregation of B and T Cell Epitopes of <i>Treponema pallidum</i> Repeat Protein K to Variable and Conserved Regions During Experimental Syphilis Infection

Morgan, Cecilia; Molini, Barbara J.; Lukehart, Sheila A.; Voorhis, Wesley C. Van

doi:10.4049/jimmunol.169.2.952

Cited by 68 publications

(83 citation statements)

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“…The high levels of tprK are consistent with our previous findings that TprK induces an early and very high level of humoral and cellular immune response during experimental infection (18,19). The differential levels of tprK transcription among the four strains correspond to the data reported by Leader et al (14), which showed earlier and higher TprK antibody reactivity in rabbits infected with Chicago and Bal 73-1 compared to Nichols infection.…”

Section: Discussionsupporting

confidence: 81%

“…Although major T-cell antigens include T. pallidum lipoproteins and endoflagellar polypeptides, TprK, TprI, and the amino-terminal conserved subfamily I peptide were also shown to be strong targets for the cellular component of the immune response (17,19,22), emphasizing again the importance of these antigens in the immune response to syphilis infection.…”

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confidence: 99%

“…pallidum (referred to here as simply T. pallidum), Nichols strain (8). Subsequently, interest in the tpr genes has continued to rise in parallel to the corpus of data relative to these potential virulence factors (4,5,13,(17)(18)(19)22). The predicted Tpr antigens can be divided into three subfamilies, based upon predicted amino acid sequence homology: subfamily I (TprC, -D, -F, and -I), subfamily II (TprE, -G, and -J), and subfamily III (TprA, -B, -H, -K, and -L).…”

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confidence: 99%

“…Although the function of the Tprs is still unknown and attempts to determine the cellular location of TprI and TprK have resulted in controversial results (10,12), several studies have highlighted the importance of these antigens during the immune response to syphilis in the rabbit model (17,19,22). Immunization with recombinant peptides based on TprI, TprF, and TprK sequences significantly alters lesion development after intradermal challenge (3,10,22); moreover, TprK possesses multiple alleles in T. pallidum isolates, conferring an impressive potential for antigenic variation and, consequently, of immune evasion (4,5).…”

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confidence: 99%

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Quantitative Analysis oftprGene Expression inTreponema pallidumIsolates: Differences among Isolates and Correlation with T-Cell Responsiveness in Experimental Syphilis

Giacani¹,

Molini²,

Godornes³

et al. 2007

Infect Immun

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Transcriptional analysis of the tpr genes in Treponema pallidum subsp. pallidum (referred to here as simply T. pallidum) has been limited to date, and yet the expression of members of this gene family is likely relevant to the pathogenesis of syphilis. Recently, immunological studies and semiquantitative mRNA analysis led to the hypothesis of the modulation of tpr gene transcription during infection and suggested that various strains of T. pallidum might differentially express these genes. In this study we developed a real-time amplification assay to quantify the tpr mRNAs with respect to the 47-kDa lipoprotein message and to compare transcript levels among four different strains of T. pallidum. In addition, we analyzed the lymphocyte responsiveness pattern toward the Tpr antigens in late experimental syphilis to identify tpr genes that had been expressed during the course of infection. The T-cell response has been implicated in clearance of treponemes from early lesions, and some of the Tprs were identified as strong targets of the cellular immune response. We show that message for many of the tpr genes can be detected in treponemes harvested at the peak of early infection. Interestingly, tprK seems to be preferentially expressed in almost every strain, and it is uniformly the target of the strongest cellular immune response. These studies demonstrate the differential expression of certain tpr genes among strains of T. pallidum, and further studies are needed to explore the relationship between tpr gene expression and the clinical course of syphilis in infected individuals.The Treponema pallidum repeat (tpr) genes constitute a promising branch of research on venereal syphilis and treponemal diseases in general (6,11,21). This paralogous gene family was identified in part by using a combination of experimental approaches (3), but all 12 members were extensively described by the genomic sequence of T. pallidum subsp. pallidum (referred to here as simply T. pallidum), Nichols strain (8). Subsequently, interest in the tpr genes has continued to rise in parallel to the corpus of data relative to these potential virulence factors (4,5,13,(17)(18)(19)22). The predicted Tpr antigens can be divided into three subfamilies, based upon predicted amino acid sequence homology: subfamily I (TprC, -D, -F, and -I), subfamily II (TprE, -G, and -J), and subfamily III (TprA, -B, -H, -K, and -L). Subfamily I and II members show, within subfamilies, common amino and carboxyl termini, separated by unique central domains that differ in sequence and length. In the Nichols strain, TprC and TprD are identical, and TprF is characterized by a truncated central domain and absence of the conserved COOH-terminal region due to a ϳ1-kb deletion and a frameshift mutation (3). Comparatively, less homology can be found among subfamily III Tprs (3). In the Nichols strain, tprA also contains a frameshift at nucleotide 712, which generates two open reading frames (ORFs), A1 and A2, for this gene (3). A reanalysis of the predicted cellular location of...

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Section: Discussionsupporting

confidence: 81%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Quantitative Analysis oftprGene Expression inTreponema pallidumIsolates: Differences among Isolates and Correlation with T-Cell Responsiveness in Experimental Syphilis

Giacani¹,

Molini²,

Godornes³

et al. 2007

Infect Immun

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“…Among Tpr family members, TprK is the best studied. A strong antibody and T cell immune response is elicited against TprK (81,82), and immunization with recombinant TprK provides partial immunity against infectious challenge (80,83). Antibodies raised against recombinant TprK can opsonize T. pallidum for phagocytosis by macrophages in vitro (80).…”

Section: The Natural History Of Syphilis Primary Syphilis -Transmissimentioning

confidence: 99%

Syphilis: using modern approaches to understand an old disease

Lukehart²

2011

J. Clin. Invest.

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194

168

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Syphilis is a fascinating and perplexing infection, with protean clinical manifestations and both diagnostic and management ambiguities. Treponema pallidum subsp. pallidum, the agent of syphilis, is challenging to study in part because it cannot be cultured or genetically manipulated. Here, we review recent progress in the application of modern molecular techniques to understanding the biological basis of this multistage disease and to the development of new tools for diagnosis, for predicting efficacy of treatment with alternative antibiotics, and for studying the transmission of infection through population networks.

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The Treponema pallidum Outer Membrane

Radolf

Kumar

2017

Current Topics in Microbiology and Immunology

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The outer membrane (OM) of Treponema pallidum, the uncultivatable agent of venereal syphilis, has long been the subject of misconceptions and controversy. Decades ago, researchers postulated that T. pallidum's poor surface antigenicity is the basis for its ability to cause persistent infection, but they mistakenly attributed this enigmatic property to the presence of a protective outer coat of serum proteins and mucopolysaccharides. Subsequent studies revealed that the OM is the barrier to antibody binding, that it contains a paucity of integral membrane proteins, and that the preponderance of the spirochete's immunogenic lipoproteins is periplasmic. Since the advent of recombinant DNA technology, the fragility of the OM, its low protein content, and the lack of sequence relatedness between T. pallidum and Gram-negative outer membrane proteins (OMPs) have complicated efforts to characterize molecules residing at the host-pathogen interface. We have overcome these hurdles using the genomic sequence in concert with computational tools to identify proteins predicted to form β-barrels, the hallmark conformation of OMPs in double-membrane organisms and evolutionarily related eukaryotic organelles. We also have employed diverse methodologies to confirm that some candidate OMPs do, in fact, form amphiphilic β-barrels and are surface-exposed in T. pallidum. These studies have led to a structural homology model for BamA and established the bipartite topology of the T. pallidum repeat (Tpr) family of proteins. Recent bioinformatics has identified several structural orthologs for well-characterized Gram-negative OMPs, suggesting that the T. pallidum OMP repertoire is more Gram-negative-like than previously supposed. Lipoprotein adhesins and proteases on the spirochete surface also may contribute to disease pathogenesis and protective immunity.

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Segregation of B and T Cell Epitopes of Treponema pallidum Repeat Protein K to Variable and Conserved Regions During Experimental Syphilis Infection

Cited by 68 publications

References 29 publications

Quantitative Analysis oftprGene Expression inTreponema pallidumIsolates: Differences among Isolates and Correlation with T-Cell Responsiveness in Experimental Syphilis

Quantitative Analysis oftprGene Expression inTreponema pallidumIsolates: Differences among Isolates and Correlation with T-Cell Responsiveness in Experimental Syphilis

Syphilis: using modern approaches to understand an old disease

The Treponema pallidum Outer Membrane

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