Syphilis is an ancient disease of humans and lagomorphs caused by two distinct but genetically closely related bacteria (>98% sequence identity based on the whole genome) of the genus Treponema. While human syphilis is well studied, little is known about the disease in the lagomorph host. Yet, comparative studies are needed to understand mechanisms in host-pathogen coevolution in treponematoses. Importantly, Treponema paraluisleporidarum-infected hare populations provide ample opportunity to study the syphilis-causing pathogen in a naturally infected model population without antibiotic treatment, data that cannot be obtained from syphilis infection in humans. We provide data on genetic diversity and are able to highlight various types of repetitions in one of the two hypervariable regions at the tp0548 locus that have not been described in the human syphilis-causing sister bacterium Treponema pallidum subsp. pallidum.

Department of Animal Health and Welfare Virology Unit Istituto Zooprofilattico Sperimentale della Lombardia e dell'Emilia Romagna Brescia Italy

Department of Biology Masaryk University Brno Czechia

Department of Biomedical Engineering Brno University of Technology Brno Czechia

Department of Environment Land Water and Planning Arthur Rylah Institute for Environmental Research Heidelberg Victoria Australia

Department of Pathology and Wildlife Diseases National Veterinary Institute Uppsala Sweden

Environmental and Conservation Sciences Murdoch University Murdoch Australia

Gene Bank of Primates Deutsches Primatenzentrum GmbH Leibniz Institute for Primate Research Göttingen Germany

Infection Biology Unit Deutsches Primatenzentrum GmbH Leibniz Institute for Primate Research Göttingen Germany

Institute for Terrestrial and Aquatic Wildlife Research University of Veterinary Medicine Hanover Foundation Hanover Germany

Institute of International Animal Health One Health Friedrich Loeffler Institut Federal Research Institute for Animal Health Greifswald Germany

Pathology Division Department of Biomedical Health Sciences Veterinary Medicine Utrecht University Utrecht the Netherlands

Primate Genetics Laboratory Deutsches Primatenzentrum GmbH Leibniz Institute for Primate Research Göttingen Germany

Professorship for International Animal Health One Health Faculty of Veterinary Medicine Justus Liebig University Giessen Germany

Wildlife Network for Disease Surveillance Bristol Veterinary School Langford Somerset United Kingdom

Wildlife Research Institute State Agency for Nature Environment and Consumer Protection North Rhine Westphalia Bonn Germany

Zobrazit více v PubMed

Arora N, Schuenemann VJ, Jäger G, Peltzer A, Seitz A, Herbig A, Strouhal M, Grillová L, Sánchez-Busó L, Kühnert D, et al. . 2016. Origin of modern syphilis and emergence of a pandemic Treponema pallidum cluster. Nat Microbiol 2:16245. doi:10.1038/nmicrobiol.2016.245 PubMed DOI

Majander K, Pfrengle S, Kocher A, Neukamm J, du Plessis L, Pla-Díaz M, Arora N, Akgül G, Salo K, Schats R, Inskip S, Oinonen M, Valk H, Malve M, Kriiska A, Onkamo P, González-Candelas F, Kühnert D, Krause J, Schuenemann VJ. 2020. Ancient bacterial genomes reveal a high diversity of Treponema pallidum strains in early modern Europe. Curr Biol 30:3788–3803. doi:10.1016/j.cub.2020.07.058 PubMed DOI

Beale MA, Marks M, Cole MJ, Lee M-K, Pitt R, Ruis C, Balla E, Crucitti T, Ewens M, Fernández-Naval C, et al. . 2021. Global phylogeny of Treponema pallidum lineages reveals recent expansion and spread of contemporary syphilis. Nat Microbiol 6:1549–1560. doi:10.1038/s41564-021-01000-z PubMed DOI PMC

Danov O, Jiménez Delgado SM, Obernolte H, Seehase S, Dehmel S, Braubach P, Fieguth H-G, Matschiner G, Fitzgerald M, Jonigk D, Knauf S, Pfennig O, Warnecke G, Wichmann J, Braun A, Sewald K. 2018. Human lung tissue provides highly relevant data about efficacy of new anti-asthmatic drugs. PLoS One 13:e0207767. doi:10.1371/journal.pone.0207767 PubMed DOI PMC

Norris, S.J. , Paster, B.J. , & Smibert, R.M. (2015). Treponema . In M.E. Trujillo, Dedysh, S. , DeVos, P. , Hedlund, B. , Kämpfer, P. , Rainey, F.A. and W.B Whitman. (ed), Bergey’s Manual of systematics of Archaea and Bacteria. 10.1002/9781118960608.gbm01249 DOI

Lumeij JT, Mikalová L, Smajs D. 2013. Is there a difference between hare syphilis and rabbit syphilis? Cross infection experiments between rabbits and hares. Vet Microbiol 164:190–194. doi:10.1016/j.vetmic.2013.02.001 PubMed DOI

Šmajs D, Zobaníková M, Strouhal M, Čejková D, Dugan-Rocha S, Pospíšilová P, Norris SJ, Albert T, Qin X, Hallsworth-Pepin K, Buhay C, Muzny DM, Chen L, Gibbs RA, Weinstock GM. 2011. Complete genome sequence of Treponema paraluiscuniculi, strain Cuniculi A: the loss of infectivity to humans is associated with genome decay. PLoS One 6:e20415. doi:10.1371/journal.pone.0020415 PubMed DOI PMC

Pětrošová H, Pospíšilová P, Strouhal M, Čejková D, Zobaníková M, Mikalová L, Sodergren E, Weinstock GM, Šmajs D. 2013. Resequencing of Treponema pallidum ssp. pallidum strains nichols and SS14: correction of sequencing errors resulted in increased separation of syphilis treponeme subclusters. PLoS One 8:e74319. doi:10.1371/journal.pone.0074319 PubMed DOI PMC

Strouhal M, Smajs D, Matejková P, Sodergren E, Amin AG, Howell JK, Norris SJ, Weinstock GM. 2007. Genome differences between Treponema pallidum subsp. Pallidum strain nichols and T. paraluiscuniculi strain Cuniculi A. Infect Immun 75:5859–5866. doi:10.1128/IAI.00709-07 PubMed DOI PMC

Nováková M, Najt D, Mikalová L, Kostková M, Vrbová E, Strouhal M, Posautz A, Knauf S, Šmajs D. 2019. First report of hare treponematosis seroprevalence of European brown hares (Lepus europaeus) in the Czech republic: seroprevalence negatively correlates with altitude of sampling areas. BMC Vet Res 15:350. doi:10.1186/s12917-019-2086-3 PubMed DOI PMC

Hisgen L, Abel L, Hallmaier-Wacker L, Lüert S, Lavazza A, Trogu T, Velarde R, Nováková M, Gyuranecz M, Ågren E, Barlow A, Šmajs D, Knauf S. 2021. The distribution of lagomorph syphilis caused by Treponema paraluisleporidarum in Europe. Eur J Wildl Res 67:92. doi:10.1007/s10344-021-01535-w DOI

Hisgen L, Abel L, Hallmaier-Wacker LK, Lueert S, Siebert U, Faehndrich M, Strauss E, Voigt U, Nováková M, Šmajs D, Knauf S. 2020. High syphilis seropositivity in European brown hares ( Lepus europaeus ), lower saxony, Germany. Transbound Emerg Dis 67:2240–2244. doi:10.1111/tbed.13551 PubMed DOI

Lukehart SA, Marra CM. 2007. Isolation and laboratory maintenance of Treponema pallidum. Curr Protoc Microbiol Chapter 12:Unit 12A.1. doi:10.1002/9780471729259.mc12a01s7 PubMed DOI

Chuma Idrissa S, Roos C, Atickem A, Bohm T, Anthony Collins D, Grillová L, Hallmaier-Wacker LK, Kazwala RR, Keyyu JD, Lüert S, Maloueki U, Oppelt J, Petrželková KJ, Piel A, Stewart FA, Šmajs D, Knauf S. 2019. Strain diversity of Treponema pallidum subsp. Pertenue suggests rare interspecies transmission in African nonhuman primates. Sci Rep 9:14243. doi:10.1038/s41598-019-50779-9 PubMed DOI PMC

Marques JP, Ferreira MS, Farelo L, Callahan CM, Hackländer K, Jenny H, Montgomery WI, Reid N, Good JM, Alves PC, Melo-Ferreira J. 2017. Mountain hare transcriptome and diagnostic markers as resources to monitor hybridization with European hares. Sci Data 4:170178. doi:10.1038/sdata.2017.178 PubMed DOI PMC

Chuma I.S, Batamuzi EK, Collins DA, Fyumagwa RD, Hallmaier-Wacker LK, Kazwala RR, Keyyu JD, Lejora IA, Lipende IF, Lüert S, Paciência FMD, Piel A, Stewart FA, Zinner D, Roos C, Knauf S. 2018. Widespread Treponema pallidum infection in nonhuman primates, Tanzania. Emerg Infect Dis 24:1002–1009. doi:10.3201/eid2406.180037 PubMed DOI PMC

Knauf S, Raphael J, Mitjà O, Lejora IAV, Chuma IS, Batamuzi EK, Keyyu JD, Fyumagwa R, Lüert S, Godornes C, Liu H, Schwarz C, Šmajs D, Grange P, Zinner D, Roos C, Lukehart SA. 2016. Isolation of Treponema DNA from necrophagous flies in a natural ecosystem. EBioMedicine 11:85–90. doi:10.1016/j.ebiom.2016.07.033 PubMed DOI PMC

Lavazza A, Cavadini P, Barbieri I, Tizzani P, Pinheiro A, Abrantes J, Esteves PJ, Grilli G, Gioia E, Zanoni M, Meneguz P, Guitton J-S, Marchandeau S, Chiari M, Capucci L. 2015. Field and experimental data indicate that the Eastern Cottontail (Sylvilagus floridanus) is susceptible to infection with European brown hare syndrome (EBHS) virus and not with rabbit haemorrhagic disease (RHD) virus. Vet Res 46:13. doi:10.1186/s13567-015-0149-4 PubMed DOI PMC

Čejková D, Zobaníková M, Chen L, Pospíšilová P, Strouhal M, Qin X, Mikalová L, Norris SJ, Muzny DM, Gibbs RA, Fulton LL, Sodergren E, Weinstock GM, Šmajs D, Lukehart S. 2012. Whole genome sequences of three Treponema pallidum ssp. Pertenue strains: yaws and syphilis treponemes differ in less than 0.2% of the genome sequence. PLoS Negl Trop Dis 6:e1471. doi:10.1371/journal.pntd.0001471 PubMed DOI PMC

Matějková P, Flasarová M, Zákoucká H, Bořek M, Křemenová S, Arenberger P, Woznicová V, Weinstock GM, Šmajs D. 2009. Macrolide treatment failure in a case of secondary syphilis: a novel A2059g mutation in the 23S rRNA gene of Treponema pallidum subsp. J Med Microbiol 58:832–836. doi:10.1099/jmm.0.007542-0 PubMed DOI

Maděránková D, Mikalová L, Strouhal M, Vadják Š, Kuklová I, Pospíšilová P, Krbková L, Koščová P, Provazník I, Šmajs D, Nascimento AL. 2019. Identification of positively selected genes in human pathogenic treponemes: syphilis-, yaws-, and bejel-causing strains differ in sets of genes showing adaptive evolution. PLoS Negl Trop Dis 13:e0007463. doi:10.1371/journal.pntd.0007463 PubMed DOI PMC

Gao F, Chen C, Arab DA, Du Z, He Y, Ho SYW. 2019. EasyCodeML: a visual tool for analysis of selection using CodeML. Ecol Evol 9:3891–3898. doi:10.1002/ece3.5015 PubMed DOI PMC

Murrell B, Wertheim JO, Moola S, Weighill T, Scheffler K, Kosakovsky Pond SL, Malik HS. 2012. Detecting individual sites subject to episodic diversifying selection. PLoS Genet 8:e1002764. doi:10.1371/journal.pgen.1002764 PubMed DOI PMC

Weaver S, Shank SD, Spielman SJ, Li M, Muse SV, Kosakovsky Pond SL. 2018. Datamonkey 2.0: a modern web application for characterizing selective and other evolutionary processes. Mol Biol Evol 35:773–777. doi:10.1093/molbev/msx335 PubMed DOI PMC

Kozlov AM, Darriba D, Flouri T, Morel B, Stamatakis A. 2019. RaxML-NG: a fast, scalable and user-friendly tool for maximum likelihood phylogenetic inference. Bioinformatics 35:4453–4455. doi:10.1093/bioinformatics/btz305 PubMed DOI PMC

Minh BQ, Schmidt HA, Chernomor O, Schrempf D, Woodhams MD, von Haeseler A, Lanfear R. 2020. IQ-TREE 2: new models and efficient methods for phylogenetic inference in the genomic era. Mol Biol Evol 37:1530–1534. doi:10.1093/molbev/msaa131 PubMed DOI PMC

Ronquist F, Teslenko M, van der Mark P, Ayres DL, Darling A, Höhna S, Larget B, Liu L, Suchard MA, Huelsenbeck JP. 2012. MrBayes 3.2: efficient bayesian phylogenetic inference and model choice across a large model space. Syst Biol 61:539–542. doi:10.1093/sysbio/sys029 PubMed DOI PMC

Zhou Z, Alikhan N-F, Sergeant MJ, Luhmann N, Vaz C, Francisco AP, Carriço JA, Achtman M. 2018. GrapeTree: visualization of core genomic relationships among 100,000 bacterial pathogens. Genome Res 28:1395–1404. doi:10.1101/gr.232397.117 PubMed DOI PMC

Hoang DT, Chernomor O, von Haeseler A, Minh BQ, Vinh LS. 2018. UFBoot2: improving the ultrafast bootstrap approximation. Mol Biol Evol 35:518–522. doi:10.1093/molbev/msx281 PubMed DOI PMC

Kalyaanamoorthy S, Minh BQ, Wong TKF, von Haeseler A, Jermiin LS. 2017. Modelfinder: fast model selection for accurate phylogenetic estimates. Nat Methods 14:587–589. doi:10.1038/nmeth.4285 PubMed DOI PMC

Gelman A, Rubin DB. 1992. Inference from Iterative simulation using multiple sequences. Statist Sci 7. doi:10.1214/ss/1177011136 DOI

Pierpaoli M, Riga F, Trocchi V, Randi E. 1999. Species distinction and evolutionary relationships of the Italian hare (Lepus corsicanus) as described by mitochondrial DNA sequencing. Mol Ecol 8:1805–1817. doi:10.1046/j.1365-294x.1999.00766.x PubMed DOI

Marques JP, Farelo L, Vilela J, Vanderpool D, Alves PC, Good JM, Boursot P, Melo-Ferreira J. 2017. Range expansion underlies historical Introgressive hybridization in the iberian hare. Sci Rep 7:40788. doi:10.1038/srep40788 PubMed DOI PMC

Seixas FA, Boursot P, Melo-Ferreira J. 2018. The genomic impact of historical hybridization with massive mitochondrial DNA introgression. Genome Biol 19:91. doi:10.1186/s13059-018-1471-8 PubMed DOI PMC

Pohjoismäki JLO, Michell C, Levänen R, Smith S. 2021. The best of both worlds: shortcutting evolution through adaptive hybridization in hares. In review. doi:10.21203/rs.3.rs-329700/v1 DOI

Houinei W, Godornes C, Kapa A, Knauf S, Mooring EQ, González-Beiras C, Watup R, Paru R, Advent P, Bieb S, Sanz S, Bassat Q, Spinola SM, Lukehart SA, Mitjà O, Lammie PJ. 2017. Haemophilus ducreyi DNA is detectable on the skin of asymptomatic children, flies and fomites in villages of Papua New Guinea. PLoS Negl Trop Dis 11:e0004958. doi:10.1371/journal.pntd.0004958 PubMed DOI PMC

Gogarten JF, Düx A, Mubemba B, Pléh K, Hoffmann C, Mielke A, Müller-Tiburtius J, Sachse A, Wittig RM, Calvignac-Spencer S, Leendertz FH. 2019. Tropical rainforest flies carrying pathogens form stable associations with social nonhuman primates. Mol Ecol 28:4242–4258. doi:10.1111/mec.15145 PubMed DOI

Grillova L, Jolley K, Šmajs D, Picardeau M. 2019. A public database for the new MLST scheme for Treponema pallidum subsp. Pallidum: surveillance and epidemiology of the causative agent of syphilis. PeerJ 6:e6182. doi:10.7717/peerj.6182 PubMed DOI PMC

Avril A, Léonard Y, Letty J, Péroux R, Guitton JS, Pontier D. 2011. Natal dispersal of European hare in a high-density population. Mammalian Biol 76:148–156. doi:10.1016/j.mambio.2010.07.001 DOI

Masseti M, Marinis AMD. 2008. Prehistoric and historic artificial dispersal of Lagomorphs on the Mediterranean Islands, p 13–25. In Alves PC, Ferrand N, Hackländer K (ed), Lagomorph biology: Evolution, Ecology, and conservation. Springer, Heidelberg.

Sokos C, Birtsas P, Papaspyropoulos KG, Giannakopoulos A, Athanasiou LV, Manolakou K, Spyrou V, Billinis C. 2015. Conservation considerations for a management measure: an integrated approach to hare rearing and release. Environ Manage 55:19–30. doi:10.1007/s00267-014-0388-6 PubMed DOI

Sánchez-García C, Pérez JA, Armenteros JA, Gaudioso VR, Tizado EJ. 2021. Survival, spatial behaviour and resting place selection of translocated iberian hares Lepus granatensis in northwestern Spain. Eur J Wildl Res 67:22. doi:10.1007/s10344-021-01464-8 DOI

Canu A, Scandura M, Luchetti S, Cossu A, Iacolina L, Bazzanti M, Apollonio M. 2013. Influence of management regime and population history on genetic diversity and population structure of brown hares (Lepus europaeus) in an Italian province. Eur J Wildl Res 59:783–793. doi:10.1007/s10344-013-0731-x DOI

Deitsch KW, Lukehart SA, Stringer JR. 2009. Common strategies for antigenic variation by bacterial, fungal and protozoan pathogens. Nat Rev Microbiol 7:493–503. doi:10.1038/nrmicro2145 PubMed DOI PMC

Castillo-Lizardo M, Henneke G, Viguera E. 2014. Replication slippage of the thermophilic DNA polymerases B and D from the Euryarchaeota Pyrococcus abyssi. Front Microbiol 5:403. doi:10.3389/fmicb.2014.00403 PubMed DOI PMC

Lukehart SA. 2008. Biology of Treponemes , p 647–659. In Holmes KK, Sparling PF, Stamm WE, Piot P, Wasserheit JN, Corey L, Cohen MS, Watts DH (ed), Sexually transmitted diseases, 4th Edition. Mc Graw Hill Medical, New York.

Chambers LC, Srinivasan S, Lukehart SA, Ocbamichael N, Morgan JL, Lowens MS, Fredricks DN, Golden MR, Manhart LE. 2019. Primary syphilis in the male urethra: a case report. Clin Infect Dis 68:1231–1234. doi:10.1093/cid/ciy771 PubMed DOI PMC

The hare syphilis agent is related to, but distinct from, the treponeme causing rabbit syphilis