Трепонема паллидум: құрылымы, патогенезі және иммундық қашалу стратегиялары

Species of bacterium

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. It is a helically coiled microorganism usually 6–15 μm long and 0.1–0.2 μm wide. 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.

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. 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.

TP0965 is a protein that is critical for membrane fusion in T. pallidum, and is located in the periplasm. TP0965 causes endothelial barrier dysfunction, a hallmark of late stage pathogenesis of syphilis. 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.

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

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." 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. 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. 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. Without the ability to grow and maintain the bacteria in a laboratory setting, discoveries regarding its metabolism and antimicrobial sensitivity were greatly impaired. However, successful long term cultivation of T. pallidum in vitro was reported in 2017. The medium TpCM 2 was used, an alteration of more simple media which previously only yielded a few weeks of culture growth. However, continuous efforts to grow T. pallidum in axenic culture have been unsuccessful, indicating that it does not satisfy Koch's postulates. 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. About 92.9% of DNA was determined to be open reading frames, 55% of which had predicted biological functions. 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. 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. 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. To avoid antibodies attacking it, the cell has few proteins exposed on the outer membrane sheath. Its chromosome is about 1000 kilobase pairs and is circular with a 52.8% G + C average. Sequencing has revealed a bundle of 12 proteins and some putative hemolysins are potential virulence factors of T. pallidum. These virulence factors are thought to contribute to the bacterium's ability to evade the immune system and cause disease.

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. 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.

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

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. 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. Many of the syphilis treatment therapies only lead to bacteriostatic results, unless larger concentrations of penicillin are used for bactericidal effects. and because T. pallidum outer membrane proteins have not been unambiguously identified. In contrast, some of the known antigens are intracellular, and antibodies are ineffective against them to clear the infection. 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.