Treponema pallidum
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Treponema pallidum, formerly known as Spirochaeta pallida,Template:Efn is a microaerophilic, gram-negative, spirochaete bacterium with subspecies that cause the diseases syphilis, bejel (also known as endemic syphilis), and yaws.<ref>Template:Cite journal</ref> It is known to be transmitted only among humans and baboons.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> T. pallidum can enter the host through mucosal membranes or open lesions in the skin and is primarily spread through sexual contact.<ref>Template:Citation</ref> It is a helically coiled microorganism usually 6–15 μm long and 0.1–0.2 μm wide. T. pallidum's lack of both a tricarboxylic acid cycle and processes for oxidative phosphorylation results in minimal metabolic activity.<ref>Template:Cite journal</ref> As a chemoorganoheterotroph, Treponema pallidum is an obligate parasite that acquires its glucose carbon source from its host. Glucose can be used not only as a primary carbon source but also in glycolytic mechanisms to generate ATP needed to power the bacterium given its minimal genome.<ref>Template:Cite journal</ref> 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 related disorder. The ability of T. pallidum to avoid host immune defenses has allowed for stealth pathogenicity.<ref>Template:Cite journal</ref> The unique outer membrane structure and minimal expression of surface proteins of T. pallidum has made vaccine development difficult. Treponema pallidum can be treated with high efficacy by antibiotics that inhibit bacterial cell wall synthesis such as the beta-lactam antimicrobial penicillin-G.<ref>Template:Citation</ref>
SubspeciesEdit
Three subspecies of T. pallidum are known:<ref name=Marks2014>Template:Cite journal</ref>
- Treponema pallidum pallidum, which causes syphilis
- T. p. endemicum, which causes bejel or endemic syphilis
- T. p. pertenue, which causes yaws
The three subspecies causing yaws, bejel, and syphilis are morphologically and serologically indistinguishable.<ref name="NBK7716">Template:Cite book</ref> The three subspecies can be distinguished by genetics, using restriction fragment length polymorphism (RFLP), which utilizes techniques such as PCR, restriction digest and gel electrophoresis.<ref name="pmid32160272">Template:Cite journal</ref> Genes TprC, TprI, and the 5' flanking region of tpp15 can be used to differentiate between the three subspecies based on DNA fragment lengths and location of bands in gel electrophoresis.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> 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.<ref name=Giacani2014>Template:Cite journal</ref> Disease transmittance in subspecies T. p. endemicum and T. p. pertenue is considered non-venereal.<ref>Template:Citation</ref> 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.<ref name="NBK7716"/>
Laboratory identificationEdit
Treponema pallidum was first microscopically identified in syphilitic chancres by Fritz Schaudinn and Erich Hoffmann at the Charité in Berlin in 1905.<ref name="Schaudinn1905">Template:Cite journal</ref> Historically, this bacterium was identified in the clinical laboratory through visualization in dark field microscopy.<ref>Template:Cite journal</ref> This bacterium can be detected with special stains, such as the Dieterle stain. T. pallidum is also detected by serology, including nontreponemal VDRL, rapid plasma reagin, treponemal antibody tests (FTA-ABS), T. pallidum immobilization reaction, and syphilis TPHA test.<ref name="Microbiology">Template:Cite book</ref>
MicrobiologyEdit
PhysiologyEdit
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Treponema pallidum is a helically shaped bacterium with high motility consisting of an outer membrane, peptidoglycan layer, inner membrane, protoplasmic cylinder, and periplasmic space.<ref name="NBK7716"/> 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.<ref name=Peeling2017>Template:Cite journal</ref> It has an endoflagellum (periplasmic flagellum) consisting of four main polypeptides, a core structure, and a sheath.<ref>Template:Cite journal</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>Template:Cite journal</ref> 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.<ref name="Norris-2001">Template:Cite journal</ref><ref name=Liu2010>Template:Cite journal</ref> The outer membrane's treponemal ligands' main function is attachment to host cells, with functional and antigenic relatedness between ligands.<ref>Template:Cite journal</ref> The genus Treponema has ribbons of cytoskeletal cytoplasmic filaments that run the length of the cell just underneath the cytoplasmic membrane.
Outer membraneEdit
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">Template:Cite book</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"/>
TP0126Edit
The TP0126 protein has been linked to the outer membrane protein family (OMP). This protein will sit in the outer membrane like a porin, which is supported by circular dichroism recombinant TP0126, and will increase the virulence factor.<ref name=":2">Template:Cite journal</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">Template:Cite journal</ref><ref name=":2" /> This protein is encoded by the tp0126 gene, which is conserved over all strains of T. pallidum. <ref name=":3" />
TP0326Edit
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.<ref name="Hawley-2021">Template:Cite journal</ref>
TP0453Edit
TP0453 is a 287 amino acid protein associated with the inner membrane of the microbe's outer membrane.<ref name="Chen22">Template:Cite journal</ref> This protein lacks the extensive beta sheet structure that is characteristic of other membrane proteins, and does not traverse the outer membrane.<ref>Template:Cite journal</ref> This protein's function has been hypothesized to be involved with control of nutrient uptake.<ref>Template:Cite journal</ref>
TP0624Edit
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">Template:Cite journal</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" />
TP0751Edit
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">Template:Cite journal</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">Template:Cite journal</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" />
TP0965Edit
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>Template:Cite journal</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 endothelial layer.<ref>Template:Cite journal</ref>
Treponema repeat family of proteinsEdit
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.<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">Template:Cite journal</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>Template:Cite journal</ref><ref name="Tang-2022">Template:Cite journal</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" />
CultureEdit
In the past century since its initial discovery, culturing the bacteria in vitro has been difficult.<ref name="Edmondson2018">Template:Cite journal</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">Template:Cite journal</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 minimal essential medium (MEM) with CMRL 1066, a complex tissue culture medium.<ref name="Edmondson2018" /> With development, new discoveries about T. pallidum'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">Template:Cite journal</ref> However, continuous efforts to grow T. pallidum in axenic culture have been unsuccessful, indicating that it does not satisfy Koch's postulates.<ref>Template:Cite journal</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" />
GenomeEdit
The genome of T. pallidum was first sequenced in 1998.<ref name="Fraser98">Template:Cite journal</ref> It is characterized by its helical, corkscrew-like shape.<ref>Template:Cite book</ref> T. pallidum is not obtainable in a pure culture, meaning that this sequencing played an important role in filling gaps of understanding regarding the microbes' functions. The DNA sequences of T. pallidum species are more than 99.7% identical, and PCR-based assays are effective at differentiating these species.<ref name="Smajs2018">Template:Cite journal</ref><ref name="linkinghub.elsevier.com">Template:Cite journal</ref> About 92.9% of DNA was determined to be open reading frames, 55% of which had predicted biological functions.<ref name="Norris-2001" /> T. pallidum was found to rely on its host for many molecules typically provided by biosynthetic pathways, and it is missing genes responsible for encoding key enzymes in oxidative phosphorylation and the tricarboxylic acid cycle.<ref>Template:Cite book</ref> The T. pallidum group and its reduced genome is likely the result of various adaptations, such that it no longer contains the ability to synthesize fatty acids, nucleic acids, and amino acids, instead relying on its mammalian hosts for these materials.<ref name="ReferenceA" /> The recent sequencing of the genomes of several spirochetes permits a thorough analysis of the similarities and differences within this bacterial phylum and within the species.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> The chromosomes of the T. pallidum species are small, about 1.14 Mbp. It has one of the smallest bacterial genomes and has limited metabolic capabilities, reflecting its adaptation through genome reduction to the rich environment of mammalian tissue. It conserves almost 99.8% of its small genome, and uses its constantly mutating protein TprK to avoid immune response from its host.<ref>Template:Cite journal</ref> To avoid antibodies attacking it, the cell has few proteins exposed on the outer membrane sheath.<ref>Template:Harvnb</ref> Its chromosome is about 1000 kilobase pairs and is circular with a 52.8% G + C average.<ref name=Fraser98/> Sequencing has revealed a bundle of 12 proteins and some putative hemolysins are potential virulence factors of T. pallidum.<ref name=Weinstock98>Template:Cite journal</ref> These virulence factors are thought to contribute to the bacterium's ability to evade the immune system and cause disease.<ref name=Weinstock98/>
Clinical significanceEdit
The clinical features of syphilis, yaws, and bejel occur in multiple stages that affect the skin. The skin lesions observed in the early stage last for weeks or months. The skin lesions are highly infectious, and the spirochetes in the lesions are transmitted by direct contact. The lesions regress as the immune response develops against T. pallidum. The latent stage that results can last a lifetime in many cases. In a few cases, the disease exits latency and enters a tertiary phase, in which destructive lesions of skin, bone, and cartilage ensue. Unlike yaws and bejels, syphilis in its tertiary stage often affects the heart, eyes, and nervous system, as well.<ref name=Giacani2014/>
SyphilisEdit
{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}} Treponema pallidum pallidum is a motile spirochete that is generally acquired by close sexual contact, entering the host via breaches in squamous or columnar epithelium. The organism can also be transmitted to a fetus by transplacental passage during the later stages of pregnancy, giving rise to congenital syphilis.<ref>Template:Cite journal</ref> The helical structure of T. p. pallidum allows it to move in a corkscrew motion through mucous membranes or enter minuscule breaks in the skin. In women, the initial lesion is usually on the labia, the walls of the vagina, or the cervix; in men, it is on the shaft or glans of the penis.<ref name="NBK7716" /> It gains access to the host's blood and lymph systems through tissue and mucous membranes. In more severe cases, it may gain access to the host by infecting the skeletal bones and central nervous system of the body.<ref name="NBK7716"/>
The incubation period for a T. p. pallidum infection is usually around 21 days, but can range from 10 to 90 days.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
YawsEdit
{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}} The causative agent of yaws is Treponema pallidum pertenue, which is transmissible by direct physical contact between infected people.<ref>Template:Cite journal</ref> Yaws is not sexually transmitted, and occurs in tropical, humid environments of Africa, Pacific Islands, Asia and South America.<ref name=":1">Template:Cite journal</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Unlike syphilis, which displays vertical transmission, one strain of T. p. pertenue researched was not vertically transmissible in a guinea pig model, and yaws cannot be spread from mother to offspring.<ref>Template:Cite journal</ref><ref name=":1" /> Yaws appears as skin lesions, usually papules, commonly on the lower extremities, but present in other areas such as the arms, trunk and hands.<ref name=":0">Template:Cite journal</ref> Three stages of yaws disease have been documented: primary yaws which presents as inflamed sores on the lower body, secondary yaws which presents as a variety of skin abnormalities along with bone inflammation, and tertiary yaws, also referred to as latent yaws, which occurs when T. p. pertenue is serologically detected in the host but no clinical signs are displayed until relapse, which often occurs years later.<ref>Template:Cite journal</ref><ref name=":0" /> Yaws is treated with antibiotics such as azithromycin and benzathine penicillin-G.<ref>Template:Cite journal</ref>
BejelEdit
Bejel is caused by Treponema pallidum endemicum and is a disease is that endemic in hot and dry climates. The transmission path has not been fully mapped, however infections are thought to be transmitted via direct contact with lesion secretions or fomites rather than by sexual transmission.<ref>Template:Cite journal</ref> Bejel typically causes skin lesions, which first appear as small ulcers in the mouth, and secondary lesions that form in the oropharynx, or around the nipples of nursing women.<ref name="linkinghub.elsevier.com"/> Bejel can be treated with benzathine penicillin-G.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>
TreatmentEdit
During the early 1940s, rabbit models in combination with the drug penicillin allowed for a long-term drug treatment. These experiments established the groundwork that modern scientists use for syphilis therapy. Penicillin can inhibit T. pallidum in 6–8 hours, though the cells still remain in lymph nodes and regenerate. Penicillin is not the only drug that can be used to inhibit T. pallidum; any β-lactam antibiotics or macrolides can be used.<ref name="Fantry">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> The T. pallidum strain 14 has built-in resistance to some macrolides, including erythromycin and azithromycin. Resistance to macrolides in T. pallidum strain 14 is believed to derive from a single-point mutation that increased the organism's livability.<ref name="Stamm-2010">Template:Cite journal</ref> Many of the syphilis treatment therapies only lead to bacteriostatic results, unless larger concentrations of penicillin are used for bactericidal effects.<ref name="Fantry" /><ref name="Stamm-2010" /> Penicillin overall is the most recommended antibiotic by the Centers for Disease Control, as it shows the best results with prolonged use. It can inhibit and may even kill T. pallidum at low to high doses, with each increase in concentration being more effective.<ref name="Stamm-2010"/> The Guideline Development Group has recommended the development of a new treatment, a short course treatment that is administered orally and can cross the placental barriers in pregnant women.<ref>Template:Cite book</ref>
VaccineEdit
No vaccine for syphilis is available as of 2024, but doxycycline postexposure prophylaxis can be used to prevent infections.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> The outer membrane of T. pallidum has too few surface proteins for an antibody to be effective. Efforts to develop a safe and effective syphilis vaccine have been hindered by uncertainty about the relative importance of humoral and cellular mechanisms to protective immunity,<ref>Template:Cite journal</ref> and because T. pallidum outer membrane proteins have not been unambiguously identified.<ref name="pmid17890130">Template:Cite journal</ref><ref name="pmid24135571" >Template:Cite journal</ref> In contrast, some of the known antigens are intracellular, and antibodies are ineffective against them to clear the infection.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> In the last century, several prototypes have been developed, and while none of them provided protection from the infection, some prevented bacteria from disseminating to distal organs and promoted accelerated healing.<ref>Template:Cite journal</ref>
NotesEdit
ReferencesEdit
Further readingEdit
External linksEdit
Template:Gram-negative non-proteobacterial bacterial diseases