Chlamydia trachomatis () is a Gram-negative, anaerobic bacterium responsible for chlamydia and trachoma. C. trachomatis exists in two forms, an extracellular infectious elementary body (EB) and an intracellular non-infectious reticulate body (RB). The EB attaches to host cells and enter the cell using effector proteins, where it transforms into the metabolically active RB. Inside the cell, RBs rapidly replicate before transitioning back to EBs, which are then released to infect new host cells.
The earliest description of C. trachomatis was in 1907 by Stanislaus von Prowazek and Ludwig Halberstädter as a protozoan. It was later thought to be a virus due to its small size and inability to grow in laboratories. It was not until 1966 when it was discovered as a bacterium by electron microscopy after its internal structures were visually observed.
There are currently 18 serovars of C. trachomatis, each associated with specific diseases affecting mucosal cells in genital tracts and ocular systems. Infections are often asymptomatic, but can lead to severe complications such as pelvic inflammatory disease in women and epididymitis in men. The bacterium also causes urethritis, conjunctivitis, and lymphogranuloma venereum in both sexes. C. trachomatis genitourinary infections are diagnosed more frequently in women than in men, with the highest prevalence occurring in females aged 15 to 19 years of age. Infants born from mothers with active chlamydia infections have a pulmonary infection rate that is less than 10%. Globally, approximately 84 million people are affected by C. trachomatis eye infections, with 8 million cases resulting in blindness. C. trachomatis is the leading infectious cause of blindness and the most common sexually transmitted bacterium.
The impact of C. trachomatis on human health has been driving vaccine research since its discovery. Currently, no vaccines are available, largely due to the complexity of the immunological pathways involved in C. trachomatis, which remain poorly understood. However, C. trachomatis infections may be treated with several antibiotics, but Doxycycline is the preferred option.
Description Chlamydia trachomatis is a gram-negative bacterium that replicates exclusively within a host cell, making it an obligate intracellular pathogen. Over the course of its life cycle, C. trachomatis takes on two distinct forms to facilitate infection and replication. Elementary bodies (EBs) are 200 to 400 nanometers across and are surrounded by a rigid cell wall that enables them to survive in an extracellular form. When an EB encounters a susceptible host cell, it binds to the cell surface and is internalized. The second form, reticulate bodies (RBs) are 600 to 1500 nanometers across, and are found only within host cells. RBs have increased metabolic activity and are adapted for replication. Neither form is motile.
The evolution of C. trachomatis includes a reduced genome of approximately 1.04 megabases, encoding approximately 900 genes. In addition to the chromosome that contains most of the genome, nearly all C. trachomatis strains carry a 7.5 kilobase plasmid that contains 8 genes. The role of this plasmid is unknown, although strains without the plasmid have been isolated, suggesting it is not essential for bacterial survival. Several important metabolic functions are not encoded in the C. trachomatis genome and are instead scavenged from the host cell.
Carbohydrate metabolism C. trachomatis has a reduced metabolic capacity due to its smaller genome, which lacks genes for many biosynthetic pathways including those required for complete carbohydrate metabolism. The bacterium is largely dependent on the host cell for metabolic intermediates and energy, particularly in the form of adenosine triphosphate (ATP). C. trachomatis lacks several enzymes necessary for independent glucose metabolism, and instead utilizes two ATP/ADP translocases (Npt1 and Npt2) to import ATP from the host cell. Other metabolites including amino acids, nucleotides, and lipids are also transported from the host.
A critical enzyme involved in glycolysis, hexokinase, is absent in C. trachomatis, preventing the production of glucose-6-phosphate (G6P). Instead, G6P from the host cell is taken up by the metabolically active reticulate bodies (RBs) through a G6P transporter (UhpC antiporter). Although C. trachomatis lacks a complete independent glycolysis pathway, it has genes encoding for all the enzymes required for the Pentose Phosphate Pathway (PPP), gluconeogenesis, and glycogen synthesis and degradation.
A suppressor of glycolysis, p53, is expressed less frequently in C. trachomatis-infected cells, increasing the rate at which glycolysis occurs, even in the presence of oxygen. As a result, C. trachomatis infection is associated with increased production of pyruvate, lactate, and glutamate by the host cell due to activity of the pyruvate dehydrogenase kinase 2 enzyme limiting conversion of pyruvate to acetyl-coenzyme A. The pyruvate is instead turned into lactate, which allows the bacterium to grow almost unobstructed by immune response due to the acidic properties of lactate. Excess glycolytic products are, in turn, brought into the host's PPP to create nucleotides and for biosynthesis, again feeding the growth needs of the bacterium. This type of growth is very similar to the Warburg effect observed in cancer cells.
Life cycle
Like other Chlamydia species, C. trachomatis has a life cycle consisting of two morphologically distinct forms. First, C. trachomatis attaches to a new host cell as a small spore-like form called the elementary body. The elementary body enters the host cell, surrounded by a host vacuole, called an inclusion. Within the inclusion, C. trachomatis transforms into a larger, more metabolically active form called the reticulate body. The reticulate body substantially modifies the inclusion, making it a more hospitable environment for rapid replication of the bacteria, which occurs over the following 30 to 72 hours. The massive number of intracellular bacteria then transition back to resistant elementary bodies before causing the cell to rupture and being released into the environment. These new elementary bodies are then shed in the semen or released from epithelial cells of the female genital tract and attach to new host cells.
Classification Chlamydia trachomatis are bacteria in the genus Chlamydia, a group of obligate intracellular parasites of eukaryotic cells. Chlamydial cells cannot carry out energy metabolism and they lack biosynthetic pathways.Becker, Y. (1996). Molecular evolution of viruses: Past and present (4th ed.). Dordrecht: Kluwer Academic. Retrieved from https://www.ncbi.nlm.nih.gov/books/NBK8091/.
Chlamydia trachomatis strains are generally divided into three biovars based on the type of human disease they cause. Each biovar is further subdivided into several serovars based on the surface antigens recognized by the immune system. Serovars A through C cause trachoma, which is the world's leading cause of preventable infectious blindness.Burton, Matthew J.; Trachoma: an overview, British Medical Bulletin, Volume 84, Issue 1, 1 December 2007, Pages 99–116, https://doi.org/10.1093/bmb/ldm034 Serovars D through K infect the genital tract, causing pelvic inflammatory disease, ectopic pregnancies, and infertility. Serovars L1 through L3 cause an invasive infection of the lymph nodes near the genitals, called lymphogranuloma venereum.
Chlamydia trachomatis is thought to have diverged from other Chlamydia species around 6 million years ago. This genus contains a total of nine species: C. trachomatis, C. muridarum, C. pneumoniae, C. pecorum, C. suis, C. abortus, C. felis, C. caviae, and C. psittaci. The closest relative to C. trachomatis is C. muridarum, which infects mice. C. muridarum was formerly known as the "mouse pneumonitis" (MoPn) biovar of C. trachomatis. C. trachomatis along with C. pneumoniae have been found to infect humans to a greater extent. C. trachomatis exclusively infects humans. C. pneumoniae is found to also infect horses, marsupials, and frogs. Some of the other species can have a considerable impact on human health due to their known zoonotic transmission.
Role in disease
Clinical signs and symptoms of C. trachomatis infection in the genitalia present as the chlamydia infection, which may be asymptomatic or may resemble a gonorrhea infection. Both are common causes of multiple other conditions including pelvic inflammatory disease and urethritis.
Chlamydia trachomatis is the single most important infectious agent associated with blindness (trachoma), and it also affects the eyes in the form of inclusion conjunctivitis and is responsible for about 19% of adult cases of conjunctivitis.
Chlamydia trachomatis in the lungs presents as the chlamydia pneumoniae respiratory infection and can affect all ages.
Pathogenesis Elementary bodies are generally present in the semen of infected men and vaginal secretions of infected women. When they come into contact with a new host cell, the elementary bodies bind to the cell via interaction between adhesins on their surface and several host receptor proteins and heparan sulfate proteoglycans. Once attached, the bacteria inject various effector proteins into the host cell using a type three secretion system. These effectors trigger the host cell to take up the elementary bodies and prevent the cell from triggering apoptosis. Within 6 to 8 hours after infection, the elementary bodies transition to reticulate bodies and a number of new effectors are synthesized. These effectors include a number of proteins that modify the inclusion membrane (Inc proteins), as well as proteins that redirect host vesicles to the inclusion. 8 to 16 hours after infection, another set of effectors are synthesized, driving acquisition of nutrients from the host cell. At this stage, the reticulate bodies begin to divide, coinciding with the expansion of the inclusion. If several elementary bodies have infected a single cell, their inclusions will fuse at this point to create a single large inclusion in the host cell. From 24 to 72 hours after infection, reticulate bodies transition to elementary bodies which are released either by lysis of the host cell or extrusion of the entire inclusion into the host genital tract.
Virulence factors The chlamydial plasmid, a DNA molecule existing separately from the genome of C. trachomatis, functions to enhance genetic diversity via the genes encoded. The plasmid gene protein 3 (pgp3) has been linked to the establishment of persistent infection within the genital tract by suppressing the host immune response.
Polymorphic outer membrane proteins (Pmp proteins) on the surface of C. trachomatis use tropism to bind specific host cell receptors, which in turn initiates infection. Pmp proteins B, D, and H have been most associated with eliciting a pro-inflammatory response through the release of cytokines.
CPAF (Chlamydia Protease-like Activity Factor) functions by preventing the host from triggering the proper immune response. C. trachomatis use of CPAF targets and cleaves proteins that restructure the Golgi apparatus and activate DNA repair so that C. trachomatis is able to use the host cell machinery and proteins to its advantage.
Presentation Most people infected with C. trachomatis are asymptomatic. However, the bacteria can present in one of three ways: genitourinary (genitals), pulmonary (lungs), and ocular (eyes).
Genitourinary cases can include genital discharge, vaginal bleeding, itchiness (pruritus), painful urination (dysuria), among other symptoms. Often, symptoms are similar to those of a urinary tract infection.