Treponema pallidum explained

Treponema pallidum, formerly known as Spirochaeta pallida, is a microaerophilic spirochaete bacterium with subspecies that cause the diseases syphilis, bejel (also known as endemic syphilis), and yaws. It is known to be transmitted only among humans[1] and baboons.[2] It is a helically coiled microorganism usually 6–15 μm long and 0.1–0.2 μm wide.[1] T. pallidums lack of both a tricarboxylic acid cycle and processes for oxidative phosphorylation results in minimal metabolic activity.[3] The treponemes have cytoplasmic and outer membranes. Using light microscopy, treponemes are visible only by using dark-field illumination. T. pallidum consists of three subspecies, T. p. pallidum, T. p. endemicum, and T. p. pertenue, each of which has a distinct associated disease.[4]

Subspecies

Three subspecies of T. pallidum are known:[5]

The three subspecies causing yaws, bejel, and syphilis are morphologically and serologically indistinguishable.[1] These bacteria were originally classified as members of separate species, but DNA hybridization analysis indicates they are members of the same species. Treponema carateum, the cause of pinta, remains a separate species because no isolate is available for DNA analysis.[6] Disease transmittance in subspecies T. p. endemicum and T. p. pertenue is considered non-venereal.[7] T. p. pallidum is the most invasive pathogenic subspecies, while T. carateum is the least invasive of the species. T. p. endemicum and T. p. pertenue are intermediately invasive.[1]

Microbiology

Physiology

Treponema pallidum is a helically shaped bacterium with high motility consisting of an outer membrane, peptidoglycan layer, inner membrane, protoplasmic cylinder, and periplasmic space.[1] It is often described as Gram negative, but its outer membrane lacks lipopolysaccharide, which is found in the outer membrane of other Gram-negative bacteria.[8] It has an endoflagellum (periplasmic flagellum) consisting of four main polypeptides, a core structure, and a sheath.[9] The flagellum is located within the periplasmic space and wraps around the protoplasmic cylinder. T. pallidum's outer membrane has the most contact with host cells and contains few transmembrane proteins, limiting antigenicity, while its cytoplasmic membrane is covered in lipoproteins.[10] The outer membrane's treponemal ligands' main function is attachment to host cells, with functional and antigenic relatedness between ligands.[11] The genus Treponema has ribbons of cytoskeletal cytoplasmic filaments that run the length of the cell just underneath the cytoplasmic membrane.

Outer membrane

The outer membrane (OM) of T. pallidum has several features that have made it historically difficult to research. These include details such as its low protein content, its fragility, and that it contains fewer gene sequences related to other gram negative outer membranes.[12] Progress has been made using genomic sequencing and advanced computational models. The treponemal outer membrane proteins are key factors for the bacterium's pathogenesis, persistence, and immune evasion strategies. The relatively low protein content prevents antigen recognition by the immune system and the proteins that do exist protrude out of the OM, enabling its interaction with the host. Treponema's reputation as a "stealth pathogen" is primarily due to this unique OM structure, which serves to evade immune detection.[12]

TP0326

TP0326 is an ortholog of the β-barrel assembly machine Bam A. BamA apparatus inserts newly synthetized and exported outer membrane proteins into the outer membrane [13]

TP0965

TP0965 is a protein that is critical for membrane fusion in T. pallidum, and is located in the periplasm.[14] TP0965 causes endothelial barrier dysfunction, a hallmark of late-stage pathogenesis of syphilis.[15] It does this by reducing the expression of tight junction proteins, which in turn increases the expression of adhesion molecules and endothelial cell permeability, which eventually leads to disruption of the endothelial layer.[16]

TP0453

TP0453 is a 287 amino acid protein associated with the inner membrane of the microbe's outer membrane.[14] This protein lacks the extensive beta sheet structure that is characteristic of other membrane proteins, and does not traverse the outer membrane.[17] This protein's function has been hypothesized to be involved with control of nutrient uptake.[18]

TP0624

Outer Membrane Protein A (OmpA) domain-containing proteins are necessary for maintaining structural integrity in Gram-negative bacteria. These domains contain peptidoglycan binding sites which creates a "structural bridge between the peptidoglycan layer and the outer memebrane."[19] The protein TP0624 found in T. pallidum has been proposed to facilitate this structural link, as well as interactions between outer membrane proteins and corresponding domains on the thin peptidoglycan layer.

Treponema repeat family of proteins

The Treponema repeat family of proteins (Tpr) are proteins expressed during the infection process. Tprs are formed by a conserved N-terminal domain, an amino-terminal stretch of about 50 amino acids, a central variable region, and a conserved C-terminal domain. The many different types of Tpr include TprA, TprB, TprC, TprD, and TprE, but variability of TprK is the most relevant due to the immune escape characteristics it allows.[20]

Antigen variation in TprK is regulated by gene conversion. In this way,  fragments of the seven variable regions (V1–V7) present in TprK and the 53 donor sites of TprD can be combined to produce new structured sequences.[21] TprK antigen variation can help T. pallidum to evade a strong host immune reaction and can also allow the reinfection of individuals. This is possible because the newly structured proteins can avoid antibody-specific recognition.

To introduce more phenotypic diversity, T. pallidum may undergo phase variation. This process mainly happens in TprF, TprI, TprG, TprJ, and TprL, and it consists of a reversible expansion or contraction of polymeric repeats. These size variations can help the bacterium to quickly adapt to its microenvironment, dodge immune response, or even increase affinity to its host.

Culture

In the past century since its initial discovery, culturing the bacteria in vitro has been difficult.[22] Without the ability to grow and maintain the bacteria in a laboratory setting, discoveries regarding its metabolism and antimicrobial sensitivity were greatly impaired.[12]

Notes and References

  1. Book: Radolf . Justin D. . Treponema . Baron . Samuel . 978-0-9631172-1-2 . NBK7716 . 13 February 2019 . University of Texas Medical Branch at Galveston . 1996 . 4th . Galveston (TX) . 21413263.
  2. Harper . Fyumagwa . Hoare . Wambura . Coppenhaver . Sapolsky . Alberts . Tung . Rogers . Kilewo . Batamuzi . Leendertz . Armelagos . Knauf . Kristin N. . Robert D. . Richard . Philemon N. . Dorian H. . Robert M. . Susan C. . Jenny . Jeffrey . Morris . Emmanuel K. . Fabian H. . George J. . Sascha . 2012. Treponema pallidum Infection in the Wild Baboons of East Africa: Distribution and Genetic Characterization of the Strains Responsible . PLOS ONE . 7. 12 . e50882 . 10.1371/journal.pone.0050882 . free . 23284649 . 3527465 . 2012PLoSO...750882H .
  3. Norris . Cox . Weinstock . Steven J. . David L.. George M.. 2001. Biology of Treponema pallidum: Correlation of Functional Activities With Genome Sequence Data . JMMB Review . 3. 1 . 37–62. 11200228 .
  4. Centurion-Lara . Arturo . Molini . Barbara J. . Godornes . Charmie . Sun . Eileen . Hevner . Karin . Voorhis . Wesley C. Van . Lukehart . Sheila A. . Sheila Lukehart . 1 September 2006 . Molecular Differentiation of Treponema pallidum Subspecies . Journal of Clinical Microbiology . 44 . 9 . 3377–80 . 10.1128/JCM.00784-06 . 1594706 . 16954278.
  5. Marks M, Solomon AW, Mabey DC . Endemic treponemal diseases . Transactions of the Royal Society of Tropical Medicine and Hygiene . 108 . 10 . 601–7 . October 2014 . 25157125 . 4162659 . 10.1093/trstmh/tru128.
  6. Giacani L, Lukehart SA . The endemic treponematoses . Clinical Microbiology Reviews . 27 . 1 . 89–115 . January 2014 . 24396138 . 3910905 . 10.1128/CMR.00070-13.
  7. Web site: Other Treponema pallidum infections . Immigrant and Refugee Health . 26 February 2019. Centers for Disease Control and Prevention . 12 November 2019.
  8. Peeling RW, Mabey D, Kamb ML, Chen XS, Radolf JD, Benzaken AS . Syphilis . Nature Reviews. Disease Primers . 3 . 17073 . October 2017 . 29022569 . 5809176 . 10.1038/nrdp.2017.73 .
  9. San Martin . Fabiana . Fule . Lenka . Iraola . Gregorio . Buschiazzo . Alejandro . Picardeau . Mathieu . 1 March 2023 . Diving into the complexity of the spirochetal endoflagellum . Trends in Microbiology . 31 . 3 . 294–307 . 10.1016/j.tim.2022.09.010 . 36244923 . 252916923 . 0966-842X. free .
  10. Liu J, Howell JK, Bradley SD, Zheng Y, Zhou ZH, Norris SJ . Cellular architecture of Treponema pallidum: novel flagellum, periplasmic cone, and cell envelope as revealed by cryoelectron tomography . Journal of Molecular Biology . 403 . 4 . 546–61 . November 2010 . 20850455 . 2957517 . 10.1016/j.jmb.2010.09.020 .
  11. Alderete . John F.. Baseman. Joel B. . December 1980 . Surface Characterization of Virulent Treponema pallidum . Infection and Immunity . 30 . 3. 814–823. 10.1128/iai.30.3.814-823.1980 . free . 7014451 . 551388.
  12. Book: Radolf . Justin D. . Kumar . Sanjiv . Spirochete Biology: The Post Genomic Era . The Treponema pallidum Outer Membrane . Current Topics in Microbiology and Immunology . 2018 . 415 . 1–38 . 10.1007/82_2017_44 . 0070-217X . 5924592 . 28849315. 978-3-319-89637-3 .
  13. Hawley . Kelly L. . Montezuma-Rusca . Jairo M. . Delgado . Kristina N. . Singh . Navreeta . Uversky . Vladimir N. . Caimano . Melissa J. . Radolf . Justin D. . Luthra . Amit . 8 July 2021 . Galperin . Michael Y. . Structural Modeling of the Treponema pallidum Outer Membrane Protein Repertoire: a Road Map for Deconvolution of Syphilis Pathogenesis and Development of a Syphilis Vaccine . Journal of Bacteriology . en . 203 . 15 . e0008221 . 10.1128/JB.00082-21 . 8407342 . 33972353.
  14. Chen . Jinlin . Huang . Jielite . Liu . Zhuoran . Xie . Yafeng . 27 September 2022 . Treponema pallidum outer membrane proteins: current status and prospects . Pathogens and Disease . en . 80 . 1 . 10.1093/femspd/ftac023 . 35869970 . free .
  15. McKevitt . Matthew . Brinkman . Mary Beth . McLoughlin . Melanie . Perez . Carla . Howell . Jerrilyn K. . Weinstock . George M. . Norris . Steven J. . Palzkill . Timothy . July 2005 . Genome Scale Identification of Treponema pallidum Antigens . Infection and Immunity . 73 . 7 . 4445–50 . 10.1128/iai.73.7.4445-4450.2005 . 15972547 . 1168556 .
  16. Zhang . Rui-Li . Zhang . Jing-Ping . Wang . Qian-Qiu . 16 December 2014 . Recombinant Treponema pallidum Protein Tp0965 Activates Endothelial Cells and Increases the Permeability of Endothelial Cell Monolayer . PLOS ONE . 9 . 12 . e115134 . 10.1371/journal.pone.0115134 . 25514584 . 4267829 . 2014PLoSO...9k5134Z . free .
  17. Hazlett . Karsten R. O. . Cox . David L. . Decaffmeyer . Marc . Bennett . Michael P. . Desrosiers . Daniel C. . La Vake . Carson J. . La Vake . Morgan E. . Bourell . Kenneth W. . Robinson . Esther J. . Brasseur . Robert . Radolf . Justin D. . September 2005 . TP0453, a concealed outer membrane protein of Treponema pallidum, enhances membrane permeability . Journal of Bacteriology . 187 . 18 . 6499–6508 . 10.1128/JB.187.18.6499-6508.2005 . 1236642 . 16159783.
  18. Luthra . Amit . Zhu . Guangyu . Desrosiers . Daniel C. . Eggers . Christian H. . Mulay . Vishwaroop . Anand . Arvind . McArthur . Fiona A. . Romano . Fabian B. . Caimano . Melissa J. . Heuck . Alejandro P. . Malkowski . Michael G. . Radolf . Justin D. . 2 December 2011 . The transition from closed to open conformation of Treponema pallidum outer membrane-associated lipoprotein TP0453 involves membrane sensing and integration by two amphipathic helices . The Journal of Biological Chemistry . 286 . 48 . 41656–68 . 10.1074/jbc.M111.305284 . 1083-351X . 3308875 . 21965687 . free .
  19. Parker . Michelle L. . Houston . Simon . Wetherell . Charmaine . Cameron . Caroline E. . Boulanger . Martin J. . 10 November 2016 . The Structure of Treponema pallidum Tp0624 Reveals a Modular Assembly of Divergently Functionalized and Previously Uncharacterized Domains . PLOS ONE . en . 11 . 11 . e0166274 . 10.1371/journal.pone.0166274 . 5104382 . 27832149 . 2016PLoSO..1166274P . free .
  20. Centurion-Lara . A. . Castro . C. . Barrett . L. . Cameron . C. . Mostowfi . M. . Van Voorhis . W. C. . Lukehart . S. A. . 15 February 1999 . Treponema pallidum major sheath protein homologue Tpr K is a target of opsonic antibody and the protective immune response . The Journal of Experimental Medicine . 189 . 4 . 647–656 . 10.1084/jem.189.4.647 . 2192927 . 9989979.
  21. Tang . Yun . Zhou . Yingjie . He . Bisha . Cao . Ting . Zhou . Xiangping . Ning . Lichang . Chen . En . Li . Yumeng . Xie . Xiaoping . Peng . Binfeng . Hu . Yibao . Liu . Shuangquan . 19 October 2022 . Investigation of the immune escape mechanism of Treponema pallidum . Infection . 51 . 2 . 305–321 . en . 10.1007/s15010-022-01939-z . 36260281 . 252994863 .
  22. Edmondson DG, Hu B, Norris SJ . June 2018 . Long-Term in Vitro Culture of the Syphilis Spirochete Treponema pallidum subsp. pallidum . mBio . 9 . 3 . 10.1128/mBio.01153-18 . 6020297 . 29946052.

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