Editing Treponema pallidum (section)

== Microbiology ==
===Physiology===
[[File:Treponema pallidum Bacteria (Syphilis).jpg|thumb|Electron micrograph image of ''T. pallidum'', highlighted in gold.]]
''Treponema pallidum'' is a helically shaped bacterium with high [[motility]] consisting of an outer membrane, [[Peptidoglycan|peptidoglycan layer]], [[Nuclear envelope|inner membrane]], [[protoplasm]]ic cylinder, and [[Periplasm|periplasmic space]].<ref name="NBK7716"/> It is often described as [[Gram-negative bacteria|gram-negative]], but its outer membrane lacks [[lipopolysaccharide]], which is found in the outer membrane of other gram-negative bacteria.<ref name=Peeling2017>{{cite journal |vauthors=Peeling RW, Mabey D, Kamb ML, Chen XS, Radolf JD, Benzaken AS |title=Syphilis |journal=Nature Reviews. Disease Primers |volume=3 |pages=17073 |date=October 2017 |pmid=29022569 |pmc=5809176 |doi=10.1038/nrdp.2017.73 }}</ref> It has an endoflagellum (periplasmic flagellum) consisting of four main [[polypeptide]]s, a core structure, and a sheath.<ref>{{Cite journal |last1=San Martin |first1=Fabiana |last2=Fule |first2=Lenka |last3=Iraola |first3=Gregorio |last4=Buschiazzo |first4=Alejandro |last5=Picardeau |first5=Mathieu |date=1 March 2023 |title=Diving into the complexity of the spirochetal endoflagellum |journal=Trends in Microbiology |volume=31 |issue=3 |pages=294–307 |doi=10.1016/j.tim.2022.09.010 |pmid=36244923 |s2cid=252916923 |issn=0966-842X|doi-access=free }}</ref> The flagellum is located within the periplasmic space and wraps around the protoplasmic cylinder. The peptidoglycan layer interacts with the endoflagellum which may aid in motility.<ref>{{Cite journal |last1=Izard |first1=Jacques |last2=Renken |first2=Christian |last3=Hsieh |first3=Chyong-Ere |last4=Desrosiers |first4=Daniel C. |last5=Dunham-Ems |first5=Star |last6=La Vake |first6=Carson |last7=Gebhardt |first7=Linda L. |last8=Limberger |first8=Ronald J. |last9=Cox |first9=David L. |last10=Marko |first10=Michael |last11=Radolf |first11=Justin D. |date=2009-12-15 |title=Cryo-Electron Tomography Elucidates the Molecular Architecture of Treponema pallidum , the Syphilis Spirochete |journal=Journal of Bacteriology |language=en |volume=191 |issue=24 |pages=7566–7580 |doi=10.1128/JB.01031-09 |issn=0021-9193 |pmc=2786590 |pmid=19820083}}</ref> ''T. pallidum''<nowiki/>'s outer membrane has the most contact with host cells and contains few [[transmembrane protein]]s, limiting [[antigenicity]], while its cytoplasmic membrane is covered in lipoproteins.<ref name="Norris-2001">{{Cite journal |last1=Norris |first1=Steven J. |last2=Cox |first2=David L. |last3=Weinstock |first3=George M. |date=2001 |title=Biology of ''Treponema pallidum'': Correlation of Functional Activities With Genome Sequence Data |url=https://www.caister.com/backlist/jmmb/v/v3/v3n1/03.pdf |journal=JMMB Review |volume=3 |issue=1 |pages=37–62 |pmid=11200228}}</ref><ref name=Liu2010>{{cite journal |vauthors=Liu J, Howell JK, Bradley SD, Zheng Y, Zhou ZH, Norris SJ |title=Cellular architecture of ''Treponema pallidum'': novel flagellum, periplasmic cone, and cell envelope as revealed by cryoelectron tomography |journal=Journal of Molecular Biology |volume=403 |issue=4 |pages=546–61 |date=November 2010 |pmid=20850455 |pmc=2957517 |doi=10.1016/j.jmb.2010.09.020 }}</ref> The outer membrane's treponemal ligands' main function is attachment to host cells, with functional and antigenic relatedness between ligands.<ref>{{Cite journal|last1=Alderete |first1=John F.|last2=Baseman|first2=Joel B. |date=December 1980 |title=Surface Characterization of Virulent ''Treponema pallidum'' |journal=Infection and Immunity |volume=30 |issue=3|pages=814–823|doi=10.1128/iai.30.3.814-823.1980 |doi-access=free  |pmid=7014451 |pmc=551388}}</ref> 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.<ref name="Radolf-2018">{{Cite book |last1=Radolf |first1=Justin D. |last2=Kumar |first2=Sanjiv |title=Spirochete Biology: The Post Genomic Era |chapter=The ''Treponema pallidum'' Outer Membrane |series=Current Topics in Microbiology and Immunology |date=2018 |volume=415 |pages=1–38 |doi=10.1007/82_2017_44 |issn=0070-217X |pmc=5924592 |pmid=28849315|isbn=978-3-319-89637-3 }}</ref> 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.<ref name="Radolf-2018" /> ''Treponema's'' reputation as a "stealth pathogen" is primarily due to this unique OM structure, which serves to evade immune detection.<ref name="Radolf-2018"/>

=====TP0126=====

The TP0126 protein has been linked to the outer membrane protein family (OMP). This protein will sit in the outer membrane like a [[Porin (protein)|porin]], which is supported by [[circular dichroism]] recombinant TP0126, and will increase the virulence factor.<ref name=":2">{{Cite journal |last1=Giacani |first1=Lorenzo |last2=Brandt |first2=Stephanie L. |last3=Ke |first3=Wujian |last4=Reid |first4=Tara B. |last5=Molini |first5=Barbara J. |last6=Iverson-Cabral |first6=Stefanie |last7=Ciccarese |first7=Giulia |last8=Drago |first8=Francesco |last9=Lukehart |first9=Sheila A. |last10=Centurion-Lara |first10=Arturo |date=June 2015 |title=Transcription of TP0126, Treponema pallidum putative OmpW homolog, is regulated by the length of a homopolymeric guanosine repeat |journal=Infection and Immunity |volume=83 |issue=6 |pages=2275–2289 |doi=10.1128/IAI.00360-15 |issn=1098-5522 |pmc=4432754 |pmid=25802057}}</ref> Researchers have classified the TP0126 protein in this class due to the homology between the protein and the porins of the OMPs.<ref name=":3">{{Cite journal |last1=Haynes |first1=Austin M. |last2=Godornes |first2=Charmie |last3=Ke |first3=Wujian |last4=Giacani |first4=Lorenzo |date=August 2019 |title=Evaluation of the Protective Ability of the Treponema pallidum subsp. pallidum Tp0126 OmpW Homolog in the Rabbit Model of Syphilis |journal=Infection and Immunity |volume=87 |issue=8 |pages=e00323–19 |doi=10.1128/IAI.00323-19 |issn=1098-5522 |pmc=6652746 |pmid=31182617}}</ref><ref name=":2" /> This protein is encoded by the tp0126 gene, which is conserved over all strains of ''T. pallidum.'' <ref name=":3" />

===== TP0326 =====
TP0326 is an [[Sequence homology|ortholog]] of the β-barrel assembly machine [[Bam A]]. BamA apparatus  inserts newly synthetized and exported outer membrane proteins into the outer membrane.<ref name="Hawley-2021">{{Cite journal |last1=Hawley |first1=Kelly L. |last2=Montezuma-Rusca |first2=Jairo M. |last3=Delgado |first3=Kristina N. |last4=Singh |first4=Navreeta |last5=Uversky |first5=Vladimir N. |last6=Caimano |first6=Melissa J. |last7=Radolf |first7=Justin D. |last8=Luthra |first8=Amit |date=8 July 2021 |editor-last=Galperin |editor-first=Michael Y. |title=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=Journal of Bacteriology |language=en |volume=203 |issue=15 |pages=e0008221 |doi=10.1128/JB.00082-21  |pmc=8407342 |pmid=33972353}}</ref>

===== TP0453 =====
TP0453 is a 287 amino acid protein associated with the inner membrane of the microbe's outer membrane.<ref name="Chen22">{{Cite journal |last1=Chen |first1=Jinlin |last2=Huang |first2=Jielite |last3=Liu |first3=Zhuoran |last4=Xie |first4=Yafeng |date=27 September 2022 |title=''Treponema pallidum'' outer membrane proteins: current status and prospects |journal=Pathogens and Disease |language=en |volume=80 |issue=1 |doi=10.1093/femspd/ftac023 |pmid=35869970 |doi-access=free}}</ref> This protein lacks the extensive [[beta sheet]] structure that is characteristic of other membrane proteins, and does not traverse the outer membrane.<ref>{{Cite journal |last1=Hazlett |first1=Karsten R. O. |last2=Cox |first2=David L. |last3=Decaffmeyer |first3=Marc |last4=Bennett |first4=Michael P. |last5=Desrosiers |first5=Daniel C. |last6=La Vake |first6=Carson J. |last7=La Vake |first7=Morgan E. |last8=Bourell |first8=Kenneth W. |last9=Robinson |first9=Esther J. |last10=Brasseur |first10=Robert |last11=Radolf |first11=Justin D. |date=September 2005 |title=TP0453, a concealed outer membrane protein of ''Treponema pallidum'', enhances membrane permeability |journal=Journal of Bacteriology |volume=187 |issue=18 |pages=6499–6508 |doi=10.1128/JB.187.18.6499-6508.2005  |pmc=1236642 |pmid=16159783}}</ref> This protein's function has been hypothesized to be involved with control of nutrient uptake.<ref>{{Cite journal |last1=Luthra |first1=Amit |last2=Zhu |first2=Guangyu |last3=Desrosiers |first3=Daniel C. |last4=Eggers |first4=Christian H. |last5=Mulay |first5=Vishwaroop |last6=Anand |first6=Arvind |last7=McArthur |first7=Fiona A. |last8=Romano |first8=Fabian B. |last9=Caimano |first9=Melissa J. |last10=Heuck |first10=Alejandro P. |last11=Malkowski |first11=Michael G. |last12=Radolf |first12=Justin D. |date=2 December 2011 |title=The transition from closed to open conformation of ''Treponema pallidum'' outer membrane-associated lipoprotein TP0453 involves membrane sensing and integration by two amphipathic helices |journal=The Journal of Biological Chemistry |volume=286 |issue=48 |pages=41656–68 |doi=10.1074/jbc.M111.305284 |issn=1083-351X |pmc=3308875 |pmid=21965687 |doi-access=free }}</ref>

===== 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."<ref name="Parker-2016">{{Cite journal |last1=Parker |first1=Michelle L. |last2=Houston |first2=Simon |last3=Wetherell |first3=Charmaine |last4=Cameron |first4=Caroline E. |last5=Boulanger |first5=Martin J. |date=10 November 2016 |title=The Structure of ''Treponema pallidum'' Tp0624 Reveals a Modular Assembly of Divergently Functionalized and Previously Uncharacterized Domains |journal=PLOS ONE |language=en |volume=11 |issue=11 |pages=e0166274 |doi=10.1371/journal.pone.0166274  |pmc=5104382 |pmid=27832149 |bibcode=2016PLoSO..1166274P |doi-access=free }}</ref> 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]].<ref name="Parker-2016" />

=====TP0751=====

The TP0751 protein is a protein that is unique to ''T. pallidum'', and it is thought to aid in attachment to the host's extra cellular membrane.<ref name=":02">{{Cite journal |last1=Parker |first1=Michelle L. |last2=Houston |first2=Simon |last3=Pětrošová |first3=Helena |last4=Lithgow |first4=Karen V. |last5=Hof |first5=Rebecca |last6=Wetherell |first6=Charmaine |last7=Kao |first7=Wei-Chien |last8=Lin |first8=Yi-Pin |last9=Moriarty |first9=Tara J. |last10=Ebady |first10=Rhodaba |last11=Cameron |first11=Caroline E. |last12=Boulanger |first12=Martin J. |date=September 2016 |title=The Structure of Treponema pallidum Tp0751 (Pallilysin) Reveals a Non-canonical Lipocalin Fold That Mediates Adhesion to Extracellular Matrix Components and Interactions with Host Cells |journal=PLOS Pathogens |volume=12 |issue=9 |pages=e1005919 |doi=10.1371/journal.ppat.1005919 |doi-access=free |issn=1553-7374 |pmc=5040251 |pmid=27683203}}</ref> Since this protein aids in the attachment to the host, it sits on the surface of the cells, and in 2005, it was discovered that the TP0751 protein will attach to the [[laminin]] component in the host's [[extracellular matrix]].<ref name=":12">{{Cite journal |last1=Cameron |first1=Caroline E. |last2=Brouwer |first2=Nathan L. |last3=Tisch |first3=Lisa M. |last4=Kuroiwa |first4=Janelle M. Y. |date=November 2005 |title=Defining the interaction of the Treponema pallidum adhesin Tp0751 with laminin |journal=Infection and Immunity |volume=73 |issue=11 |pages=7485–7494 |doi=10.1128/IAI.73.11.7485-7494.2005 |issn=0019-9567 |pmc=1273862 |pmid=16239550}}</ref> With that, it is thought that the TP0751 protein plays a key role in dissemination with the host.<ref name=":12" /><ref name=":02" />

===== TP0965 =====
TP0965 is a protein that is critical for membrane fusion in ''T. pallidum'', and is located in the [[periplasm]].<ref name="Chen22" /> TP0965 causes endothelial barrier dysfunction, a hallmark of late-stage pathogenesis of [[syphilis]].<ref>{{Cite journal |last1=McKevitt |first1=Matthew |last2=Brinkman |first2=Mary Beth |last3=McLoughlin |first3=Melanie |last4=Perez |first4=Carla |last5=Howell |first5=Jerrilyn K. |last6=Weinstock |first6=George M. |last7=Norris |first7=Steven J. |last8=Palzkill |first8=Timothy |date=July 2005 |title=Genome Scale Identification of ''Treponema pallidum'' Antigens |journal=Infection and Immunity |volume=73 |issue=7 |pages=4445–50 |doi=10.1128/iai.73.7.4445-4450.2005 |pmc=1168556 |pmid=15972547}}</ref> 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 [[Endothelium|endothelial]] layer.<ref>{{Cite journal |last1=Zhang |first1=Rui-Li |last2=Zhang |first2=Jing-Ping |last3=Wang |first3=Qian-Qiu |date=16 December 2014 |title=Recombinant ''Treponema pallidum'' Protein Tp0965 Activates Endothelial Cells and Increases the Permeability of Endothelial Cell Monolayer |journal=PLOS ONE |volume=9 |issue=12 |pages=e115134 |bibcode=2014PLoSO...9k5134Z |doi=10.1371/journal.pone.0115134 |pmc=4267829 |pmid=25514584 |doi-access=free}}</ref>

=== 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-terminus|N-terminal domain]], an amino-terminal stretch of about 50 amino acids, a central variable region, and a conserved [[C-terminus|C-terminal domain]].<ref name="Hawley-2021" /> 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.<ref name="Centurion-Lara-1999">{{Cite journal |last1=Centurion-Lara |first1=A. |last2=Castro |first2=C. |last3=Barrett |first3=L. |last4=Cameron |first4=C. |last5=Mostowfi |first5=M. |last6=Van Voorhis |first6=W. C. |last7=Lukehart |first7=S. A. |date=15 February 1999 |title=''Treponema pallidum'' major sheath protein homologue Tpr K is a target of opsonic antibody and the protective immune response |journal=The Journal of Experimental Medicine |volume=189 |issue=4 |pages=647–656 |doi=10.1084/jem.189.4.647  |pmc=2192927 |pmid=9989979}}</ref>

Antigen variation in TprK is regulated by gene conversion. In this way, fragments of the seven variable regions (V1–V7), by nonreciprocal recombination, present in TprK and the 53 donor sites of TprD can be combined to produce new structured sequences.<ref>{{Cite journal |last1=Giacani |first1=Lorenzo |last2=Molini |first2=Barbara J. |last3=Kim |first3=Eric Y. |last4=Godornes |first4=B. Charmie |last5=Leader |first5=B. Troy |last6=Tantalo |first6=Lauren C. |last7=Centurion-Lara |first7=Arturo |last8=Lukehart |first8=Sheila A. |date=2010-04-01 |title=Antigenic variation in Treponema pallidum: TprK sequence diversity accumulates in response to immune pressure during experimental syphilis |journal=Journal of Immunology |volume=184 |issue=7 |pages=3822–3829 |doi=10.4049/jimmunol.0902788 |issn=1550-6606 |pmc=3042355 |pmid=20190145}}</ref><ref name="Tang-2022">{{Cite journal |last1=Tang |first1=Yun |last2=Zhou |first2=Yingjie |last3=He |first3=Bisha |last4=Cao |first4=Ting |last5=Zhou |first5=Xiangping |last6=Ning |first6=Lichang |last7=Chen |first7=En |last8=Li |first8=Yumeng |last9=Xie |first9=Xiaoping |last10=Peng |first10=Binfeng |last11=Hu |first11=Yibao |last12=Liu |first12=Shuangquan |date=19 October 2022 |title=Investigation of the immune escape mechanism of ''Treponema pallidum'' |journal=Infection |volume=51 |issue=2 |pages=305–321 |language=en |doi=10.1007/s15010-022-01939-z |pmid=36260281 |s2cid=252994863 }}</ref> 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.<ref name="Centurion-Lara-1999" /> This is possible because the newly structured proteins can avoid antibody-specific recognition. It is also suspected that the genes that encode for the TprK protein are essential in [[pathogenesis]] during the infection of [[syphilis]].<ref name="Centurion-Lara-1999" />

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.<ref name="Tang-2022" />

===Culture===
In the past century since its initial discovery, culturing the bacteria in vitro has been difficult.<ref name="Edmondson2018">{{cite journal |vauthors=Edmondson DG, Hu B, Norris SJ |date=June 2018 |title=Long-Term in Vitro Culture of the Syphilis Spirochete ''Treponema pallidum'' subsp. pallidum |journal=mBio |volume=9 |issue=3 |doi=10.1128/mBio.01153-18 |pmc=6020297 |pmid=29946052}}</ref> Without the ability to grow and maintain the bacteria in a laboratory setting, discoveries regarding its metabolism and [[antimicrobial]] sensitivity were greatly impaired.<ref name="Radolf-2018"/> However, successful long-term cultivation of ''T.'' ''pallidum'' in vitro was reported in 2017.<ref name="Edmondson2018" /> This was achieved using Sf1Ep epithelial cells from rabbits, which were a necessary condition for the continued multiplication and survival of the system.<ref name="Edmondson-2021">{{Cite journal |last1=Edmondson |first1=Diane G. |last2=DeLay |first2=Bridget D. |last3=Kowis |first3=Lindsay E. |last4=Norris |first4=Steven J. |date=23 February 2021 |title=Parameters Affecting Continuous In Vitro Culture of ''Treponema pallidum'' Strains |journal=mBio |volume=12 |issue=1 |pages=10.1128/mbio.03536–20 |doi=10.1128/mbio.03536-20 |pmc=8545124 |pmid=33622721}}</ref> The medium TpCM-2 was used, an alteration of more simple media which previously only yielded a few weeks of culture growth.<ref name="Edmondson-2021" /> This success was the result of switching out [[Eagle's minimal essential medium|minimal essential medium]] (MEM) with CMRL 1066, a complex tissue culture medium.<ref name="Edmondson2018" /> With development, new discoveries about ''T.'' ''pallidum''<nowiki/>'s requirements for growth and gene expression may occur and in turn, yield research beneficial for the treatment and prevention of syphilis, outside of a host.<ref name="ReferenceA">{{Cite journal |last1=Edmondson |first1=Diane G. |last2=Norris |first2=Steven J. |date=February 2021 |title=In Vitro Cultivation of the Syphilis Spirochete ''Treponema pallidum'' |journal=Current Protocols |volume=1 |issue=2 |pages=e44 |doi=10.1002/cpz1.44  |pmc=7986111 |pmid=33599121}}</ref> However, continuous efforts to grow ''T. pallidum'' in [[axenic]] culture have been unsuccessful, indicating that it does not satisfy [[Koch's postulates]].<ref>{{Cite journal |last1=Prescott |first1=Joseph |last2=Feldmann |first2=Heinz |last3=Safronetz |first3=David |date=January 2017 |title=Amending Koch's postulates for viral disease: When "growth in pure culture" leads to a loss of virulence |url=|journal=Antiviral Research |volume=137 |pages=1–5 |doi=10.1016/j.antiviral.2016.11.002  |pmc=5182102 |pmid=27832942}}</ref> The challenge likely stems from the organism's strong adaptation to residing in mammalian tissue, resulting in a reduced genome and significant impairments in metabolic and biosynthetic functions.<ref name="Edmondson-2021" />