Treponema pallidum

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Treponema pallidum
Treponema pallidum.jpg
Scientific classification OOjs UI icon edit-ltr.svg
Domain: Bacteria
Phylum: Spirochaetota
Class: Spirochaetia
Order: Spirochaetales
Family: Treponemataceae
Genus: Treponema
Species:
T. pallidum
Binomial name
Treponema pallidum

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 transmitted only among humans. [1] It is a helically coiled microorganism usually 6–15 μm long and 0.1–0.2 μm wide. [1] T. pallidum's lack of either a tricarboxylic acid cycle or oxidative phosphorylation results in minimal metabolic activity. [2] The treponemes have a cytoplasmic and an outer membrane. 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. [3]

Subspecies

Three subspecies of T. pallidum are known: [4]

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. [5] Disease transmittance in subspecies T. p. endemicum and T. p. pertenue is considered non-venereal. [6] 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

Electron micrograph image of T. pallidum, highlighted in gold. Treponema pallidum Bacteria (Syphilis).jpg
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 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. [7] It has an endoflagellum (periplasmic flagellum) consisting of four main polypeptides, a core structure, and a sheath. [8] 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. [2] [9] The outer membrane's treponemal ligands' main function is attachment to host cells, with functional and antigenic relatedness between ligands. [10] The genus Treponema has ribbons of cytoskeletal cytoplasmic filaments that run the length of the cell just underneath the cytoplasmic membrane. They are composed of the intermediate filament-like protein cytoplasmic filament protein A (CfpA). Although the filaments may be involved in chromosome structure and segregation or cell division, their precise function is unknown. [9] [11]

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. [12] 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. [17] This protein lacks the extensive beta sheet structure that is characteristic of other membrane proteins, and does not traverse the outer membrane. [18] This protein's function has been hypothesized to be involved with control of nutrient uptake. [19]

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." [20] 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. [20]

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. [13] 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. [21]

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. [22] 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. [21]

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. [22]

Culture

In the past century since its initial discovery, culturing the bacteria in vitro has been difficult. [23] Without the ability to grow and maintain the bacteria in a laboratory setting, discoveries regarding its metabolism and antimicrobial sensitivity were greatly impaired. [24] However, successful long-term cultivation of T.pallidum in vitro was reported in 2017. [23] This was achieved using Sf1Ep epithelial cells from rabbits, which were a necessary condition for the continued multiplication and survival of the system. [25] The medium TpCM-2 was used, an alteration of more simple media which previously only yielded a few weeks of culture growth. [25] This success was the result of switching out minimal essential medium (MEM) with CMRL 1066, a complex tissue culture medium. [23] 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. [26] However, continuous efforts to grow T. pallidum in axenic culture have been unsuccessful, indicating that it does not satisfy Koch's postulates. [27] 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. [25]

Genome

The chromosomes of the T. pallidum species are small, about 1.14 Mbp. Their DNA sequences are more than 99.7% identical. [28] About 92.9% of DNA was determined to be open reading frames, 55% of which had predicted biological functions. [2] The genome ofT. pallidum was first sequenced in 1998. [29] 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. 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. [30] 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. [26] 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. [31] [32] [33] T. pallidum 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. T. pallidum is characterized by its helical, corkscrew-like shape. [34] To avoid antibodies attacking it, the cell has few proteins exposed on the outer membrane sheath. [35] Its chromosome is about 1000 kilobase pairs and is circular with a 52.8% G + C average. [36] Sequencing has revealed a bundle of 12 proteins and some putative hemolysins are potential virulence factors of T. pallidum. [37] These virulence factors are thought to contribute to the bacterium's ability to evade the immune system and cause disease. [38]

Clinical significance

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. [5]

Syphilis

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. [39] 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. [1] 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. [1]

The incubation period for a T. p. pallidum infection is usually around 21 days, but can range from 10 to 90 days. [40]

Laboratory identification

Electron micrograph image of T. pallidum cultured on epithelial cells of cotton-tail rabbits. TreponemaPallidum.jpg
Electron micrograph image of T. pallidum cultured on epithelial cells of cotton-tail rabbits.

Treponema pallidum was first microscopically identified in syphilitic chancres by Fritz Schaudinn and Erich Hoffmann at the Charité in Berlin in 1905. [41] 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. [42]

Treatment

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. [43] 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. [44] Many of the syphilis treatment therapies only lead to bacteriostatic results, unless larger concentrations of penicillin are used for bactericidal effects. [43] [44] 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. [44]

Vaccine

No vaccine for syphilis is available as of 2024. 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, [45] and because T. pallidum outer membrane proteins have not been unambiguously identified. [46] [47] In contrast, some of the known antigens are intracellular, and antibodies are ineffective against them to clear the infection. [48] [49] [50] 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. [51]

Related Research Articles

<span class="mw-page-title-main">Syphilis</span> Sexually transmitted infection

Syphilis is a sexually transmitted infection caused by the bacterium Treponema pallidum subspecies pallidum. The signs and symptoms of syphilis vary depending in which of the four stages it presents. The primary stage classically presents with a single chancre though there may be multiple sores. In secondary syphilis, a diffuse rash occurs, which frequently involves the palms of the hands and soles of the feet. There may also be sores in the mouth or vagina. In latent syphilis, which can last for years, there are few or no symptoms. In tertiary syphilis, there are gummas, neurological problems, or heart symptoms. Syphilis has been known as "the great imitator" as it may cause symptoms similar to many other diseases.

<i>Neisseria gonorrhoeae</i> Species of bacterium

Neisseria gonorrhoeae, also known as gonococcus (singular) or gonococci (plural), is a species of Gram-negative diplococci bacteria isolated by Albert Neisser in 1879. It causes the sexually transmitted genitourinary infection gonorrhea as well as other forms of gonococcal disease including disseminated gonococcemia, septic arthritis, and gonococcal ophthalmia neonatorum.

<span class="mw-page-title-main">Spirochaete</span> Phylum of bacteria

A spirochaete or spirochete is a member of the phylum Spirochaetota, which contains distinctive diderm (double-membrane) Gram-negative bacteria, most of which have long, helically coiled cells. Spirochaetes are chemoheterotrophic in nature, with lengths between 3 and 500 μm and diameters around 0.09 to at least 3 μm.

<span class="mw-page-title-main">Rapid plasma reagin</span> Test for syphilis

The rapid plasma reagin test is a type of rapid diagnostic test that looks for non-specific antibodies in the blood of the patient that may indicate an infection by syphilis or related non-venereal treponematoses. It is one of several nontreponemal tests for syphilis. The term reagin means that this test does not look for antibodies against the bacterium itself, Treponema pallidum, but rather for antibodies against substances released by cells when they are damaged by T. pallidum. Traditionally, syphilis serologic testing has been performed using a nontreponemal test (NTT) such as the RPR or VDRL test, with positive results then confirmed using a specific treponemal test (TT) such as TPPA or FTA-ABS. This method is endorsed by the U.S. Centers for Disease Control and Prevention (CDC) and is the standard in many parts of the world. After screening for syphilis, a titer can be used to track the progress of the disease over time and its response to therapy.

Pinta is a human skin disease caused by infection with the spirochete Treponema carateum, which is morphologically and serologically indistinguishable from the bacterium that causes syphilis. The disease was previously known to be endemic to Mexico, Central America, and South America; it may have been eradicated since, with the latest case occurring in Brazil in 2020.

<i>Treponema</i> Genus of bacteria

Treponema is a genus of spiral-shaped bacteria. The major treponeme species of human pathogens is Treponema pallidum, whose subspecies are responsible for diseases such as syphilis, bejel, and yaws. Treponema carateum is the cause of pinta. Treponema paraluiscuniculi is associated with syphilis in rabbits. Treponema succinifaciens has been found in the gut microbiome of traditional rural human populations.

<i>Borrelia burgdorferi</i> Species of bacteria

Borrelia burgdorferi is a bacterial species of the spirochete class in the genus Borrelia, and is one of the causative agents of Lyme disease in humans. Along with a few similar genospecies, some of which also cause Lyme disease, it makes up the species complex of Borrelia burgdorferi sensu lato. The complex currently comprises 20 accepted and 3 proposed genospecies. B. burgdorferi sensu stricto exists in North America and Eurasia and until 2016 was the only known cause of Lyme disease in North America. Borrelia species are Gram-negative.

<span class="mw-page-title-main">Nonvenereal endemic syphilis</span> Medical condition

Bejel, or endemic syphilis, is a chronic skin and tissue disease caused by infection by the endemicum subspecies of the spirochete Treponema pallidum. Bejel is one of the "endemic treponematoses", a group that also includes yaws and pinta. Typically, endemic trepanematoses begin with localized lesions on the skin or mucous membranes. Pinta is limited to affecting the skin, whereas bejel and yaws are considered to be invasive because they can also cause disease in bone and other internal tissues.

<i>Moraxella catarrhalis</i> Species of bacterium

Moraxella catarrhalis is a fastidious, nonmotile, Gram-negative, aerobic, oxidase-positive diplococcus that can cause infections of the respiratory system, middle ear, eye, central nervous system, and joints of humans. It causes the infection of the host cell by sticking to the host cell using trimeric autotransporter adhesins.

<i>Borrelia</i> Genus of bacteria

Borrelia is a genus of bacteria of the spirochete phylum. Several species cause Lyme disease, also called Lyme borreliosis, a zoonotic, vector-borne disease transmitted by ticks. Other species of Borrelia cause relapsing fever, and are transmitted by ticks or lice, depending on the species of bacteria. A few Borrelia species as Candidatus Borrelia mahuryensis harbor intermediate genetic features between Lyme disease and relapsing fever Borrelia. The genus is named after French biologist Amédée Borrel (1867–1936), who first documented the distinction between a species of Borrelia, B. anserina, and the other known type of spirochete at the time, Treponema pallidum. This bacterium must be viewed using dark-field microscopy, which make the cells appear white against a dark background. Borrelia species are grown in Barbour-Stoenner-Kelly medium. Of 52 known species of Borrelia, 20 are members of the Lyme disease group, 29 belong to the relapsing fever group, and two are members of a genetically distinct third group typically found in reptiles. A proposal has been made to split the Lyme disease group based on genetic diversity and move them to their own genus, Borelliella, but this change is not widely accepted. This bacterium uses hard and soft ticks and lice as vectors. Testing for the presence of the bacteria in a human includes two-tiered serological testing, including immunoassays and immunoblotting.

The fluorescent treponemal antibody absorption (FTA-ABS) test is a diagnostic test for syphilis. Using antibodies specific for the Treponema pallidum species, such tests would be assumed to be more specific than non-treponemal testing such as VDRL but have been shown repeatedly to be sensitive but not specific for the diagnosis of neurosyphilis in cerebrospinal fluid (CSF). In addition, FTA-ABS turns positive earlier and remains positive longer than VDRL. Other treponemes, such as T. pertenue, may also produce a positive FTA-ABS. The ABS suffix refers particularly to a processing step used to remove nonspecific antispirochetal antibodies present in normal serum.

In, molecular genetics, an ORFeome refers to the complete set of open reading frames (ORFs) in a genome. The term may also be used to describe a set of cloned ORFs. ORFs correspond to the protein coding sequences (CDS) of genes. ORFs can be found in genome sequences by computer programs such as GENSCAN and then amplified by PCR. While this is relatively trivial in bacteria the problem is non-trivial in eukaryotic genomes because of the presence of introns and exons as well as splice variants.

<span class="mw-page-title-main">Lyme disease microbiology</span>

Lyme disease, or borreliosis, is caused by spirochetal bacteria from the genus Borrelia, which has 52 known species. Three main species are the main causative agents of the disease in humans, while a number of others have been implicated as possibly pathogenic. Borrelia species in the species complex known to cause Lyme disease are collectively called Borrelia burgdorferisensu lato (s.l.) not to be confused with the single species in that complex Borrelia burgdorferi sensu stricto which is responsible for nearly all cases of Lyme disease in North America.

Porphyromonas gingivalis belongs to the phylum Bacteroidota and is a nonmotile, Gram-negative, rod-shaped, anaerobic, pathogenic bacterium. It forms black colonies on blood agar.

Treponema denticola is a Gram-negative, obligate anaerobic, motile and highly proteolytic spirochete bacterium. It is one of four species of oral spirochetes to be reliably cultured, the others being Treponema pectinovorum, Treponema socranskii and Treponema vincentii. T. denticola dwells in a complex and diverse microbial community within the oral cavity and is highly specialized to survive in this environment. T. denticola is associated with the incidence and severity of human periodontal disease. Treponema denticola is one of three bacteria that form the Red Complex, the other two being Porphyromonas gingivalis and Tannerella forsythia. Together they form the major virulent pathogens that cause chronic periodontitis. Having elevated T. denticola levels in the mouth is considered one of the main etiological agents of periodontitis. T. denticola is related to the syphilis-causing obligate human pathogen, Treponema pallidum subsp. pallidum. It has also been isolated from women with bacterial vaginosis.

<span class="mw-page-title-main">Prokaryotic cytoskeleton</span> Structural filaments in prokaryotes

The prokaryotic cytoskeleton is the collective name for all structural filaments in prokaryotes. It was once thought that prokaryotic cells did not possess cytoskeletons, but advances in visualization technology and structure determination led to the discovery of filaments in these cells in the early 1990s. Not only have analogues for all major cytoskeletal proteins in eukaryotes been found in prokaryotes, cytoskeletal proteins with no known eukaryotic homologues have also been discovered. Cytoskeletal elements play essential roles in cell division, protection, shape determination, and polarity determination in various prokaryotes.

<span class="mw-page-title-main">History of syphilis</span>

The first recorded outbreak of syphilis in Europe occurred in 1494/1495 in Naples, Italy, during a French invasion. Because it was spread geographically by French troops returning from that campaign, the disease was known as "French disease", and it was not until 1530 that the term "syphilis" was first applied by the Italian physician and poet Girolamo Fracastoro. The causative organism, Treponema pallidum, was first identified by Fritz Schaudinn and Erich Hoffmann in 1905 at the Charité Clinic in Berlin. The first effective treatment, Salvarsan, was developed in 1910 by Sahachiro Hata in the laboratory of Paul Ehrlich. It was followed by the introduction of penicillin in 1943.

<span class="mw-page-title-main">Meningeal syphilis</span> Medical condition

Meningeal syphilis is a chronic form of syphilis infection that affects the central nervous system. Treponema pallidum, a spirochate bacterium, is the main cause of syphilis, which spreads drastically throughout the body and can infect all its systems if not treated appropriately. Treponema pallidum is the main cause of the onset of meningeal syphilis and other treponemal diseases, and it consists of a cytoplasmic and outer membrane that can cause a diverse array of diseases in the central nervous system and brain.

Spiral bacteria, bacteria of spiral (helical) shape, form the third major morphological category of prokaryotes along with the rod-shaped bacilli and round cocci. Spiral bacteria can be subclassified by the number of twists per cell, cell thickness, cell flexibility, and motility. The two types of spiral cells are spirillum and spirochete, with spirillum being rigid with external flagella, and spirochetes being flexible with internal flagella.

Sheila Lukehart is an American physician who is Emeritus Professor of Medicine at the University of Washington. Her research covered immune responses and the pathogenesis of syphilis. In 2023, she was elected a Fellow of the American Society for Microbiology.

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