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Extracellular loops in OMPs of Gram-negative bacteria are known to be highly variable. We examined the sequence diversity of \u03b2-barrel-encoding regions of\n tprC<\/jats:italic>\n ,\n tprD<\/jats:italic>\n , and\n bamA<\/jats:italic>\n in 31 specimens from Cali, Colombia; San Francisco, California; and the Czech Republic and compared them to allelic variants in the 41 reference genomes in the NCBI database. To establish a phylogenetic framework, we used\n T.\u00a0pallidum<\/jats:named-content>\n 0548 (\n tp0548<\/jats:italic>\n ) genotyping and\n tp0558<\/jats:italic>\n sequences to assign strains to the Nichols or SS14 clades. We found that (i) \u03b2-barrels in clinical strains could be grouped according to allelic variants in\n T.\u00a0pallidum<\/jats:named-content>\n subsp.\n pallidum<\/jats:named-content>\n reference genomes; (ii) for all three OMP loci, clinical strains within the Nichols or SS14 clades often harbored \u03b2-barrel variants that differed from the Nichols and SS14 reference strains; and (iii) OMP variable regions often reside in predicted extracellular loops containing B-cell epitopes. On the basis of structural models, nonconservative amino acid substitutions in predicted transmembrane \u03b2-strands of\n T.\u00a0pallidum<\/jats:named-content>\n repeat C (TprC) and TprD2 could give rise to functional differences in their porin channels. OMP profiles of some clinical strains were mosaics of different reference strains and did not correlate with results from enhanced molecular typing. Our observations suggest that human host selection pressures drive\n T.\u00a0pallidum<\/jats:named-content>\n subsp.\n pallidum<\/jats:named-content>\n OMP diversity and that genetic exchange contributes to the evolutionary biology of\n T.\u00a0pallidum<\/jats:named-content>\n subsp.\n pallidum<\/jats:named-content>\n . They also set the stage for topology-based analysis of antibody responses to OMPs and help frame strategies for syphilis vaccine development.\n <\/jats:p>\n \n IMPORTANCE<\/jats:bold>\n Despite recent progress characterizing outer membrane proteins (OMPs) of\n Treponema pallidum<\/jats:named-content>\n , little is known about how their surface-exposed, \u03b2-barrel-forming domains vary among strains circulating within high-risk populations. In this study, sequences for the \u03b2-barrel-encoding regions of three OMP loci,\n tprC<\/jats:italic>\n ,\n tprD<\/jats:italic>\n , and\n bamA<\/jats:italic>\n , in\n T.\u00a0pallidum<\/jats:named-content>\n subsp.\n pallidum<\/jats:named-content>\n isolates from a large number of patient specimens from geographically disparate sites were examined. Structural models predict that sequence variation within \u03b2-barrel domains occurs predominantly within predicted extracellular loops. Amino acid substitutions in predicted transmembrane strands that could potentially affect porin channel function were also noted. Our findings suggest that selection pressures exerted within human populations drive\n T.\u00a0pallidum<\/jats:named-content>\n subsp.\n pallidum<\/jats:named-content>\n OMP diversity and that recombination at OMP loci contributes to the evolutionary biology of syphilis spirochetes. These results also set the stage for topology-based analysis of antibody responses that promote clearance of\n T.\u00a0pallidum<\/jats:named-content>\n subsp.\n pallidum<\/jats:named-content>\n and frame strategies for vaccine development based upon conserved OMP extracellular loops.\n <\/jats:p>","DOI":"10.1128\/mbio.01006-18","type":"journal-article","created":{"date-parts":[[2018,6,11]],"date-time":"2018-06-11T03:26:55Z","timestamp":1528687615000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":40,"title":["Sequence Variation of Rare Outer Membrane Protein \u03b2-Barrel Domains in Clinical Strains Provides Insights into the Evolution of\n Treponema pallidum<\/i>\n subsp.\n pallidum<\/i>\n , the Syphilis Spirochete"],"prefix":"10.1128","volume":"9","author":[{"given":"Sanjiv","family":"Kumar","sequence":"first","affiliation":[{"name":"Department of Medicine, UConn Health, Farmington, Connecticut, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Melissa J.","family":"Caimano","sequence":"additional","affiliation":[{"name":"Department of Medicine, UConn Health, Farmington, Connecticut, USA"},{"name":"Department of Pediatrics, UConn Health, Farmington, Connecticut, USA"},{"name":"Department of Molecular Biology and Biophysics, UConn Health, Farmington, Connecticut, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arvind","family":"Anand","sequence":"additional","affiliation":[{"name":"Department of Medicine, UConn Health, Farmington, Connecticut, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abhishek","family":"Dey","sequence":"additional","affiliation":[{"name":"Department of Medicine, UConn Health, Farmington, Connecticut, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kelly L.","family":"Hawley","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, UConn Health, Farmington, Connecticut, USA"},{"name":"Division of Pediatric Infectious Diseases, Connecticut Children\u2019s Medical Center, Hartford, Connecticut, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Morgan E.","family":"LeDoyt","sequence":"additional","affiliation":[{"name":"Department of Medicine, UConn Health, Farmington, Connecticut, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carson J.","family":"La Vake","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, UConn Health, Farmington, Connecticut, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adriana R.","family":"Cruz","sequence":"additional","affiliation":[{"name":"Centro Internacional de Entrenamiento e Investigaciones Medicas (CIDEIM), Cali, Colombia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lady G.","family":"Ramirez","sequence":"additional","affiliation":[{"name":"Centro Internacional de Entrenamiento e Investigaciones Medicas 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