Instruct: Given a question, retrieve relevant documents that answer the question.
Query: Can you cure orientia tsutsugamushi?
O. tsutsugamushi is naturally maintained in the mite population by transmission from female to its eggs (transovarial transmission), and from the eggs to larvae and then to adults (transtadial transmission). The mite larvae, called chiggers, are natural ectoparasites of rodents. Humans get infected upon accidental contact with infected chiggers. A scar-like scab called eschar is a good indicator of infection, but is not ubiquitous. The bacterium is endemic to the so-called Tsutsugamushi Triangle, a region covering the Russian Far East in the north, Japan in the east, northern Australia in the south, and Afghanistan in the west. One million infections are estimated to occur annually. Antibiotics such as azithromycin and doxycycline are the main prescription drugs; chloramphenicol and tetracyclin are also effective. Diagnosis of the infection is difficult and requires laborious techniques such as Weil–Felix test, rapid immunochromatographic test, immunofluorescence assays, and polymerase chain reaction. There is no working vaccine.
For more than 60 years there was no consensus on the choice of name – both R. orientalis and R. tsutsugamushi were equally used. Akira Tamura and colleagues reported in 1991 the structural differences of the bacterium from Rickettsia species that warranted separate genus, and proposed the name Orientia tsutsugamushi.[19] Finally in 1995, they made a new classification based on the morphological and biochemical properties, formally creating the new name O. tsutsugamushi.[20]
In the past, rickettsioses were considered to be caused by species of Rickettsia. However, scrub typhus is still considered a rickettsiosis, even though the causative organism has been reclassified from "Rickettsia tsutsugamushi" to "Orientia tsutsugamushi".
Leptotrombidium () is a genus of mites in the family Trombiculidae, that are able to infect humans with scrub typhus ("Orientia tsutsugamushi" infection) through their bite. The larval form (called chiggers) feeds on rodents, but also occasionally humans and other large mammals. They are related to the harvest mites of the North America and Europe.
Although the harvest mite chigger usually do not carry diseases in North American temperate climates, "Leptotrombidium deliense" is considered a dangerous pest in East Asia and the South Pacific because it often carries "Orientia tsutsugamushi", the tiny bacterium that causes scrub typhus, which is known alternatively as the Japanese river disease, scrub disease, or "tsutsugamushi". The mites are infected by the "Rickettsia" passed down from parent to offspring before eggs are laid in a process called transovarial transmission. Symptoms of scrub typhus in humans include fever, headache, muscle pain, cough, and gastrointestinal symptoms.
O. tsutsugamushi is most often detected from blood serum using Weil–Felix test. Weil–Felix test is the most simple and rapid test, but it is not sensitive and specific as it detects any kind of rickettsial infection. More sensitive tests such as rapid immunochromatographic test (RICT), immunofluorescence assays (IFA), enzyme-linked immunosorbent assay (ELISA), and DNA analysis using polymerase chain reaction (PCR) are used.[35][27] IFA is regarded as the gold standard test, as it gives reliable result. However, it is expensive and not specific for different rickettsial bacteria.[75] ELISA and PCR can detect O. tsutsugamushi-specific proteins such as the 56-kDa protein and GroEL so that they are highly specific and sensitive.[76] On the other hand, they are highly sophisticated and expensive techniques.
Genome comparison shows only 657 core genes among the different strains.[32] With about 42-47% of repetitive sequences, O. tsutsugamushi has the most highly repeated bacterial genome sequenced so far.[33] Repeated DNA sequence includes short repetitive sequences, transposable elements (including insertion sequence elements, miniature inverted-repeat transposable elements, a Group II intron), and a greatly amplified integrative and conjugative element (ICE) called the rickettsial amplified genetic element (RAGE).[31] RAGE is also found in other rickettsial bacteria. In O. tsutsugamushi, however, RAGE contains a number of genes including tra genes typical of Type IV secretion systems and gene for ankyrin repeat–containing protein. Ankyrin repeat–containing proteins are secreted through a Type I secretion system into the host cell. The precise role of Type IV secretion system in O. tsutsugamushi is not known. It may be involved in horizontal gene transfer between the different strains.[1]
Scrub typhus or bush typhus is a form of typhus caused by the intracellular parasite "Orientia tsutsugamushi", a Gram-negative α-proteobacterium of family Rickettsiaceae first isolated and identified in 1930 in Japan.
O.tsutsugamushi is naturally transmitted in the mite population belonging to the genus Leptotrombidium. It can be transmitted from female to its eggs through the process called transovarial transmission, and from the eggs to larvae and adults through the process of transtadial transmission. Thus, the bacterial life cycle is maintained entirely in mites. Infection to rodents and humans is an accidental transmission from the bite of mite larvae, and not required for reproduction or survival the bacterium. In fact, in rodents and humans the transmission is stopped, and the bacterium meets a dead end.[26]
O.tsutsugamushi infection can be treated with antibiotics such as azithromycin, chloramphenicol, doxycycline, rifampicin, roxithromycin, and tetracyclin. Doxycycline is the most commonly used and is considered as the drug of choice because of high efficacy and quick action. But in pregnant women and babies it is contraindicated, and azithromycin is the drug of choice. In Southeast Asia, where doxycycline and chloramphenicol resistance have been experienced, azithromycin is recommended for all patients.[62] A randomized controlled trial and systematic review showed that azithromycin is the safest medication.[63][64]
Enormous antigenic variation in "Orientia tsutsugamushi" strains is now recognized, and immunity to one strain does not confer immunity to another. Any scrub typhus vaccine should give protection to all the strains present locally, to give an acceptable level of protection. A vaccine developed for one locality may not be protective in another, because of antigenic variation. This complexity continues to hamper efforts to produce a viable vaccine.
The aetiology of the disease was never apparent. In 1908 a mite theory of the transmission of tsutsugamushi disease was postulated by Taichi Kitashima and Mikinosuke Miyajima.[8] In 1915 a British zoologist Stanley Hirst suggested that the larvae of mite Microtrombidium akamushi (later renamed Leptotrombidium akamushi) which he found on the ears of field mice could carry and transmit the infection.[9] In 1917 Mataro Nagayo and colleagues gave the first complete description of the developmental stages such as egg, nymph, larva, and adult of the mite; and also asserted that only the larvae bites mammals, and are thus the only carriers of the parasites.[10] But then the actual infectious agent was not known, and it was generally attributed to either a virus or a protozoan.[11]
“Scrub typhus is probably one of the most underdiagnosed and underreported febrile illnesses requiring hospitalization in the region. The absence of definitive signs and symptoms combined with a general dependence upon serological tests make the differentiation of scrub typhus from other common febrile diseases such as murine typhus, typhoid fever and leptospirosis quite difficult.”[59]
There is no complete immunity to O. tsutsugamushi infection. Enormous antigenic variation among O. tsutsugamushi strains makes the immune system unable to fully recognise them. An infected individual may develop a short-term immunity but that disappears after a few months, and immunity to one strain does not confer immunity to another.[79] An immunisation experiment was done in 1950 in which 16 volunteers still developed the infection after 11–25 months of primary infection.[81] It is now known that the longevity of immunity depends on the strains of the bacterium. When reinfection occurs with the same strain as the previous infection, there can be immunity for 5–6 years (experimentally in monkeys).[82]
No licensed O. tsutsugamushi vaccines are currently available. The first vaccines were developed in the late 1940s, but failed in the clinical trials.[77][78] Considered an ideal target, the unique 56-kDa protein itself is highly variable in its chemical composition in different strains. An effective vaccine for one strain is not useful for another. An ideal vaccine should give protection to all the strains present locally. This complexity makes it difficult to produce a usable vaccine.[79] A vaccine targeting the 47-kDa outer membrane protein (OMP) is a promising candidate with experimental success in mice against Boryong strain.[80]
Epidemic typhus is caused by the bacteria Rickettsia Prowazekii; it comes from lice. Murine Typhus is caused by the Rickettsia Typhi bacteria, from the fleas on rats. Scrub Typhus is caused by the Orientia Tsutsugamushi bacteria, from the harvest mites on humans and rodents. 
Queensland tick typhus is caused by the Rickettsia Australis bacteria, from ticks.
O. tsutsugamushi belongs to Gram-negative bacteria and is a permanent (obligate) parasite in mites. A unicellular organism, it is rod shaped and measures 0.5 to 0.8µm wide and 1.2 to 3.0µm long. Due to similarity, it was initially categorised in the genus Rickettsia, but later assigned a separate genus, Orientia,[20] which it shares (so far) only with Candidatus Orientia chuto.[21] It is larger and broader, but shorter than other rickettsial bacteria. During reproduction, it divides (by binary fission) into two daughter cells by the process of budding. While undergoing budding, it accumulates on the host cell surface unlike other bacteria. One complete budding takes 9 to 18 hours.[22]
O. tsutsugamushi has a special adaptation for surviving in the host cell by evading the host immune reaction. Once it interacts with the host cells, it causes the host cell membrane to form a transportation bubble called a clathrin-coated vesicle by which it gets transported in the cytoplasm moves. Inside the cytoplasm, it makes an exit from the vesicle (now known as an endosome) before it is destroyed (in the process of cell-eating called autophagy) by the lysosome.[39] It then moves towards the nucleus, specifically at the perinuclear region, where it starts to grow and multiply. Unlike other closely related bacteria which use actin-mediated processes for movement in the cytoplasm (called intracellular trafficking or transport), O. tsutsugamushi is unusual in using microtubule-mediated processes similar to those employed by viruses such as adenoviruses and herpes simplex viruses. Further, the escape (exocytosis) from an infected host cell is also unusual. It forms another vesicle using the host cell membrane, gives rise to small bud, and releases itself from the host cell surface while still enclosed in the vesicle. The membrane-bound bacterium is formed by interaction between cholesterol-rich lipid rafts as well as HtrA, a 47-kDa protein on the bacterial surface.[40] However, the process of budding and importance of membrane-bound bacterium are not yet understood.
The main symptom of O. tsutsugamushi infection is high (febrile) fever; however, the symptom is not unique and is similar to a group of acute undifferentiated fever, which includes those of malaria, leptospirosis, typhoid fever, murine typhus, chikungunya, and dengue fever.[65][66] This makes precise clinical diagnosis difficult, which often leads to misdiagnosis. The initial indications are fever with chills, associated with headache, muscle pain (myalgia), sweating and vomiting. The appearance of symptoms (incubation period) takes between 6 and 21 days.[53] A useful diagnosis is the presence of an inflamed scar called eschar, which is regarded as "the most useful diagnostic clue in patients with acute febrile illness". Eschar is formed on the skin where an infected mite bit, usually seen in the armpit, groin or any abdominal area. In rare cases, it can be seen on the cheek, ear lobe and dorsum of the feet.[67] But the problem is that eschar is not always present. At the highest record, only 55% of scrub typhus patients had eschar during an outbreak in south India.[68] Also that eschar is not specific to scrub typhus, as other rickettsial diseases such as Rocky Mountain spotted fever,[69] Brazilian spotted fever,[70] and Indian tick typhus.[71][72] Using DNA analysis by advanced polymerase chain reaction, different rickettsial infection can be identified from eschars.[73][74]
Scrub typhus is historically endemic to the Asia-Pacific region covering the Russian Far East and Korea in the north to northern Australia in the south and Afghanistan in the west, including islands of the western Pacific Oceans such as Japan, Taiwan, Philippines, Papua New Guinea, Indonesia, Sri Lanka, and the Indian Subcontinent. This geographic region is popularly called the Tsutsugamushi Triangle.[53] However, it has spread to Africa, Europe and South America.[60] One billion people are estimated to be at risk of infection at any moment and an average of one million cases occur every year in the Tsutsugamushi Triangle. In the absence of proper medical care, the case fatality rate can go beyond 30% to as high as 70% in some areas.[36] The burden of scrub typhus in rural areas of Asia is huge, accounting for up to 20% of febrile sickness in hospital, and seroprevalence (positive infection on blood test) over 50% of the population.[61] More than one-fifth of the population carry the bacterial antibodies, i.e., they had been infected, in endemic areas. South Korea has the highest level incidence (with its highest of 59.7 infection out of 100,000 people in 2013), followed by Japan, Thailand, and China at top of the list.[55]
Typhus group rickettsiae ("Rickettsia prowazekii", "R. typhi") react with "P. vulgaris" OX19, and scrub typhus ("Orientia tsutsugamushi") reacts with "P. mirabilis" OXK. The spotted fever group rickettsiae ("R. rickettsii", "R. africae", "R. japonica", etc.) react with "P. vulgaris" OX2 and OX19, to varying degrees, depending on the species.
The genus comprises the species "Orientia tsutsugamushi" and "Orientia chuto", which both cause scrub typhus in humans.
The causative pathogen was first identified by Naosuke Hayashi in 1920. Confident that the organism was a protozoan, Hayashi concluded, stating, "I have reached the conclusion that the virus of the disease is the species of Piroplasma [protozoan] in question... I consider the organism in Tsutsugamushi disease as a hitherto undescribed species, and at the suggestion of Dr. Henry B. Ward designate it as Theileria tsutsugamushi." [12] Discovering the similarities with the bacterium Rickettsia prowazekii, Mataro Nagayo and colleagues gave a new classification with the name Rickettsia orientalis in 1930.[13][14] (R. prowazekii is a causative bacterium of epidemic typhus first discovered by American physicians Howard Taylor Ricketts and Russell M. Wilder in 1910; and described by a Brazilian physician Henrique da Rocha Lima in 1916.[15])
In rodent and human infections, Leptotrombidium deliense is the most universal vector of O. tsutsugamushi. L. pallidum, L. fletcheri and L. scutellare are also carriers in many countries. In addition, L. akamushi is an endemic carrier in Japan, L. chiangraiensis and L. imphalum in Thailand, L. gaohuensis in China, and L. arenicola in Malaysia and Indonesia.[3] In parts of India, a different mite species, Schoengastiella ligula is also a major vector.[34] The third-stage larvae, commonly referred to as chiggers, are the only ectoparasitic stage feeding on the body fluids of rodents and other opportunistic mammals. Thus, they are the only stage in the life of mites that cause infection. Wild rats of the genus Rattus are the principal natural hosts of the chiggers.[35] Chiggers feed only once on a mammalian host. The feeding usually takes 2 to 4 days. Contrary to most parasites, they do not feed on blood, but instead on the body fluid through the hair follicles or skin pores. They possess a special feeding apparatus called stylostome on their heads. Their saliva can dissolve the host tissue around the feeding site, so that they ingest the liquefied tissue. O. tsutsugamushi is present in the salivary glands of mites and is released into the host tissue during this feeding.[36]
O. tsutsugamushi has four major surface-membrane proteins (antigens) having molecular weights 22 kDa, 47 kDa, 56 kDa and 110 kDa. A 56-kDa protein is the most important because it is not produced by any other bacteria, and is responsible for making the genetic diversity in different strains.[49] It accounts for about 10–15% of the total cell protein. The 22-kDa, 47-kDa or 110-kDa antigens are not normally detected by sophisticated diagnostic tests. But clinical tests easily detect the 56-kDa protein, making it the main target in diagnosis.[50] The protein assists the adhesion and entry of the bacterium into host cells, as well as evasion of the host's immune reaction. It varies in size from 516 to 540 amino acid residues between different strains, and its gene is about 1,550 base pairs long. It contains four hypervariable regions, indicating that it synthesise many antigenically different protein but of the same kind.[46] There are also 11-kDa and 60-kDa protein inside the bacterium which are very similar to GroES and GroEL of the bacterium Escherichia coli, but not that of Rickettsia species.[51] GroES and GroEL are heat shock proteins belonging to the family of molecular chaperones in bacteria. DNA analysis have shown that the GroES and GroEL genes are indeed present in O. tsutsugamushi with slight variation in different strain and they produce the 11-kDa and 60-kDa proteins.[52]