Dataset Information

The sequence-variable, single-copy tprK gene of Treponema pallidum Nichols strain UNC and Street strain 14 encodes heterogeneous TprK proteins.

ABSTRACT: Syphilis is a chronic infection with early relapses that are hypothesized to result from the emergence of phenotypic variants of Treponema pallidum. Recent studies demonstrated that TprK, a target of protective immunity, is heterogeneous in several T. pallidum strains, but not in Nichols strain Seattle (A. Centurion-Lara, C. Godornes, C. Castro, W. C. Van Voorhis, and S. A. Lukehart, Infect. Immun. 68:824-831, 2000). Analysis of PCR-amplified tprK from Nichols strain UNC and Street strain 14 treponemes showed that TprK has seven regions of intrastrain heterogeneity resulting from amino acid substitutions, insertions, and deletions. In contrast, analysis of PCR-amplified tprJ showed little intrastrain or interstrain heterogeneity. Reverse transcriptase PCR analysis demonstrated that mRNA transcripts representing unique polymorphic TprK proteins are present during syphilitic infection. Southern hybridization confirmed that Nichols strain UNC and Street strain 14 each contain a single copy of tprK, indicating that intrastrain heterogeneity is due to the presence of multiple treponemal subpopulations which contain a variant form of tprK.

SUBMITTER: Stamm LV

PROVIDER: S-EPMC97738 | biostudies-literature | 2000 Nov

REPOSITORIES: biostudies-literature

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The sequence-variable, single-copy tprK gene of Treponema pallidum Nichols strain UNC and Street strain 14 encodes heterogeneous TprK proteins.

Stamm L V LV Bergen H L HL

Infection and immunity 20001101 11

Syphilis is a chronic infection with early relapses that are hypothesized to result from the emergence of phenotypic variants of Treponema pallidum. Recent studies demonstrated that TprK, a target of protective immunity, is heterogeneous in several T. pallidum strains, but not in Nichols strain Seattle (A. Centurion-Lara, C. Godornes, C. Castro, W. C. Van Voorhis, and S. A. Lukehart, Infect. Immun. 68:824-831, 2000). Analysis of PCR-amplified tprK from Nichols strain UNC and Street strain 14 tre ...[more]

PMID: 11035764

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Project description:Immune evasion and disease progression of Treponema pallidum subsp. pallidum are associated with sequence diversity in the hypervariable outer membrane protein TprK. Previous attempts to study variation within TprK have sequenced at depths insufficient to fully appreciate the hypervariable nature of the protein, failed to establish linkage between the protein's seven variable regions, or were conducted on isolates passed through rabbits. As a consequence, a complete profile of tprK during infection in the human host is still lacking. Furthermore, prior studies examining how T. pallidum subsp. pallidum uses its repertoire of genomic donor sites to generate diversity within the variable regions of the tprK have yielded a partial understanding of this process due to the limited number of tprK alleles examined. In this study, we used short- and long-read deep sequencing to directly characterize full-length tprK alleles from T. pallidum subsp. pallidum collected from early lesions of patients attending two sexually transmitted infection clinics in Italy. We demonstrate that strains collected from cases of secondary syphilis contain significantly more unique variable region sequences and full-length TprK sequences than those from cases of primary syphilis. Our data, combined with recent data available on Chinese T. pallidum subsp. pallidum specimens, show the near-complete absence of overlap in TprK sequences among the 41 specimens profiled to date. We further estimate that the potential antigenic variability carried by TprK rivals that of current estimates of the human adaptive immune system. These data underscore the immunoevasive ability of TprK that allows T. pallidum subsp. pallidum to establish lifelong infection.IMPORTANCE Syphilis continues to be a significant public health issue in both low- and high-income countries, including the United States where the rate of syphilis infection has increased over the past 5 years. Treponema pallidum subsp. pallidum, the causative agent of syphilis, carries the outer membrane protein TprK that undergoes segmental gene conversion to constantly create new sequences. We performed full-length deep sequencing of TprK to examine TprK diversity in clinical T. pallidum subsp. pallidum strains. We then combined our results with data from all samples for which TprK deep sequencing results were available. We found almost no overlap in TprK sequences between different patients. Moreover, our data allowed us to estimate the total number of TprK variants that T. pallidum subsp. pallidum can potentially generate. Our results support how the T. pallidum subsp. pallidum TprK antigenic variation system is an equal adversary of the human immune system leading to pathogen persistence in the host.

Project description:BackgroundTreponema pallidum ssp. pallidum (TPA), the causative agent of syphilis, is a highly clonal bacterium showing minimal genetic variability in the genome sequence of individual strains. Nevertheless, genetically characterized syphilis strains can be clearly divided into two groups, Nichols-like strains and SS14-like strains. TPA Nichols and SS14 strains were completely sequenced in 1998 and 2008, respectively. Since publication of their complete genome sequences, a number of sequencing errors in each genome have been reported. Therefore, we have resequenced TPA Nichols and SS14 strains using next-generation sequencing techniques.Methodology/principal findingsThe genomes of TPA strains Nichols and SS14 were resequenced using the 454 and Illumina sequencing methods that have a combined average coverage higher than 90x. In the TPA strain Nichols genome, 134 errors were identified (25 substitutions and 109 indels), and 102 of them affected protein sequences. In the TPA SS14 genome, a total of 191 errors were identified (85 substitutions and 106 indels) and 136 of them affected protein sequences. A set of new intrastrain heterogenic regions in the TPA SS14 genome were identified including the tprD gene, where both tprD and tprD2 alleles were found. The resequenced genomes of both TPA Nichols and SS14 strains clustered more closely with related strains (i.e. strains belonging to same syphilis treponeme subcluster). At the same time, groups of Nichols-like and SS14-like strains were found to be more distantly related.Conclusion/significanceWe identified errors in 11.5% of all annotated genes and, after correction, we found a significant impact on the predicted proteomes of both Nichols and SS14 strains. Corrections of these errors resulted in protein elongations, truncations, fusions and indels in more than 11% of all annotated proteins. Moreover, it became more evident that syphilis is caused by treponemes belonging to two separate genetic subclusters.

Dataset Information

The sequence-variable, single-copy tprK gene of Treponema pallidum Nichols strain UNC and Street strain 14 encodes heterogeneous TprK proteins.

Publications

The sequence-variable, single-copy tprK gene of Treponema pallidum Nichols strain UNC and Street strain 14 encodes heterogeneous TprK proteins.

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