Rickettsia: Difference between revisions

Orientia
	Orientia tsutsugamushi
Scientific classification
Domain:	Bacteria
Phylum:	Proteobacteria
Class:	Alphaproteobacteria
Order:	Rickettsiales
Family:	Rickettsiaceae
Genus:	Orientia
Species:	O. tsutsugamushi
Binomial name
	Orientia tsutsugamushi; (Hayashi, 1920) (Ogata, 1929) Tamura et al., 1995

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Orientia tsutsugamushi (from Japanese tsutsuga meaning "illness", and mushi meaning "insect") is a mite-borne bacterium belonging to the family Rickettsiaceae that causes a disease called scrub typhus.^[1] It is a natural and obligate intracellular parasite of mites belonging to the family Trombiculidae.^[2]^[3] With a genome of only 2.4–2.7 Mb, it has the most repeated DNA sequences among bacterial genomes sequenced so far. The disease, scrub typhus, occurs when infected mite larvae accidentally bite humans. Primarily indicated by undifferentiated febrile illnesses, the infection is serious and often fatal.

O. tsutsugamushi infection was first reported in Japan by Hakuju Hashimoto in 1810, and to the Western world by Theobald Adrian Palm in 1878. Naosuke Hayashi was the first to describe it in 1920, giving the name Theileria tsutsugamushi. Owing to unique properties, it was renamed Orientia tsutsugamushi in 1995. Unlike other Gram-negative bacteria, it is not easily stained with Gram stain, and its cell wall is devoid of lipophosphoglycan and peptidoglycan. With highly variable membrane protein, a 56-kDa protein, the bacterium can be antigenically classified into many strains (sub-types). The classic strains are Karp (which accounts for about 50% of all infections), Gilliam (25%), Kato (less than 10%), Shimokoshi, Kuroki and Kawasaki.^[4] Within each strain, enormous variability further exists.

O. tsutsugamushi is naturally maintained in mite population by transmission from female to its eggs (transovarial transmission), and from the eggs to larvae and adults (transtadial transmission). The mite larvae, called chiggers, are ectoparasites of rodents. Humans get infected when they accidentally come in contact with infected chiggers. A scar-like scab called eschar is a good indicator of infection. The bacterium is endemic to the so-called Tsutsugamushi Triangle, covering the Asia-Pacific region from 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.

History

Scrub typhus as a disease was recorded in the 3rd century CE in China. Japanese were also familiar with the link between the infection and mites for centuries. They gave several names such as shima-mushi, akamushi (red mite) or kedani (hairy mite) disease of northern Japan, and most popularly as tsutsugamushi (from tsutsuga meaning fever or harm or noxious, and mushi meaning bug or insect). Japanese physician Hakuju Hashimoto gave the first medical account from Niigata Prefecture in 1810. He recorded the prevalence of the infection along the banks of the upper tributaries of Shinano River.^[5] The first report to the Western world was made by Theobald Adrian Palm, a physician of the Edinburgh Medical Missionary Society at Niigata, in 1878. Describing his first-hand experience, Palm wrote:

Last summer [i.e. 1877], I had the opportunity of observing a disease which, so far as I know, is peculiar to Japan, and has not yet been, described. It occurs, moreover, in certain well-marked districts, and at a particular season of the year, so that the opportunities of investigating it do not often occur. It is known here as the shima-mushi, or island-insect disease, and is so-named from the belief that it is caused by the bite or sting of some insect peculiar to certain islands in the river known as Shinagawa, which empties itself into the sea at Niigata.^[6]

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.^[7] In 1915, S. Hirst suggested that the larvae of mites Microtrombidium akamushi (later renamed Leptotrombidium akamushi) which he foundnon the ears of field mice could carry and transmit the infection.^[8] 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 concluded that only the larvae bites mammals, and are thus the only carriers of the parasites.^[9] But then the actual infectious agent was not known, and they attributed it to either a virus or a protozoan.^[10]

The causative pathogen was first identified by a Japanese biologist Naosuke Hayashi in 1920. Confident that the pathogen was a protozoan, Hayashi concluded, saying, "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." ^[11] Discovering the similarities with the bacterium Rickettsia prowazekii, Mataro Nagayo and colleagues gave anew classification and a new name Rickettsia orientalis in 1930.^[12]^[13] (R. prowazekii is a causative bacterium of epidemic typhus first discovered by American physicians Howard Taylor Ricketts and Russell M. Wilder in 1910; it was described by a Brazilian physician Henrique da Rocha Lima in 1916.^[14])

The taxonomic controversy worsened. In 1931, Norio Ogata gave the name Rickettsia tsutsugamushi,^[15] while Rinya Kawamüra and Yoso Imagawa independently introduced the name Rickettsia akamushi.^[16] Kawamüra and Imagawa discovered that the bacteria are stored in the salivary glands of mites, and that mites feed on body (lymph) fluid, thereby establishing the fact that mites transmit the infection during feeding.^[17]

Finally in 1995, Akira Tamura and colleagues made a new classification based on the morphological and biochemical properties, giving the name Orientia tsutsugamushi.^[18]

Biology

The bacterium was initially categorised in the genus Rickettsia,^[2] but is now classed in a separate genus, Orientia, which it shares with the recently described species Orientia chuto.^[19] O. tsutsugamushi is different from Rickettsial or any other Gram-negative bacteria in having a cell wall that lacks lipophosphoglycan and peptidoglycan, which are otherwise characteristics of bacteria. Its genome totally lacks the genes for lipophosphoglycan synthesis, but does contain those for peptidoglycan. In fact, there are unique genes such as PBP1, alr, dapF, and murl, which are not known in other bacteria. But peptidoglycan is synthesised in very small quantity that can hardly be detected and plays minor role in the cell wall.^[20] Other distinct features are the thicker leaflet of the cell wall, and presence of muramic acid, glucosamine, hydroxy fatty acids, and 2-keto-3-deoxyoctonic acid.^[21]

It is a unicellular organism of 0.5 µm wide and 1.2 to 3.0 µm long, and is an obligatory intracellular organism that can only be cultured in cell monolayers. The organism is highly virulent and should only be handled in a laboratory with biosafety level 3 facilities.^[22] Even though adaptation to obligate intracellular parasitism among bacteria generally results in reduced genome, O. tsutsugamushi has a genome size of about 2.0–2.7 Mb depending on the strains, which is comparatively larger than those of other members of Rickettsiaceae—200 times larger than that of Rickettsia prowazekii, a causative agent of epidemic typhus. The entire genome is distributed in a single chromosome. Whole genome sequences are available for Ikeda and Baryong strains only. The genome of Ikeda strain is 2,008,987 bp long, and contains 1,967 protein-coding genes.^[23] In Boryong strain, the genome is 2,127,051 bp long with 2,179 protein-coding genes.^[24]

Genome comparison has shown that the there are only 657 core genes among the different strains.^[25] With about 42-47% of repetitive sequences, O. tsutsugamushi has the most highly repeated bacterial genome sequenced so far.^[26] 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).^[24] 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]

Life cycle and transmission

Chigger with its stylostome (arrowhead), the feeding apparatus.

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 in mites. Infection to rodents and humans is an accidental transmission from the bite of mites, 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.^[21]

In rodent and human infections, Leptotrombidium deliense and L. akamushi are the two most important vectors of O. tsutsugamushi. In parts of India, another mite species, Schoengastiella ligula is also a major vector.^[27] 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 can cause the infection. Wild rats of the genus Rattus are the principal natural hosts of the chiggers.^[28] Chiggers feed only once on a mammal host. The feeding usually takes 2 to 4 days. They do not feed on blood, but instead on the body fluid through the hair follicles or skin pores. The saliva of chiggers dissolve 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.^[29]

Cellular invasion

O. tsutsugamushi initially attack the myeloid cells (young white blood cells) in the area of inoculation, and then the endothelial cells lining the vasculature. In blood circulation, monocytes and macrophages in all organs are the secondary targets. The parasite first attaches itself to the target cells using surface proteoglycans present on the host cell and bacterial surface proteins such as TSP56 (TSA56) and ScaC.^[30] These proteins interact with the host fibronectin to induce phagocytosis (the process of swallowing the bacterium). The ability to actually enter the host cell depends on integrin-mediated signaling and reorganisation of actin cytoskeleton.^[31]

O. tsutsugamushi has a special adaptation for surviving in the host cell by evading the host immune reaction. Once it interacts with the host, it causes the host-cell membrane to form a transportation bubble called a clathrin-coated vesicle. Once inside the cytoplasm, it makes an exit before it is destroyed (in the process of cell-eating called autophagy) by the lysosome.^[32] It moves towards the nucleus, specifically at the perinuclear region, where it starts to replicate. 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 used by viruses such as adenoviruses and herpes simplex viruses. Further, the escape 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 while still enclosed in the membrane. 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.^[33] However, the process of budding and importance of membrane-bound bacterium are not yet understood.

Strains

O. tsutsugamushi is a diverse species of bacteria. There are six basic antigenic strains, namely Gilliam, Karp, Kato, Shimokoshi, Kawasaki, and Kuroki. Karp is the most abundant strain accounting for about 50% of all infections.^[3] But in Korea, the major strain is Boryong.^[34] In addition, more than 30 different strains have been established in humans.^[26] The number is much higher if the strains in rodents and mites are taken into account. For example, a study in Japan in 1994 reported 32 strains, 14 from human patients, 12 from wild rodents, and 6 from trombiculid mites. The different strains exert different levels of virulence, and the most virulent is KN-3, which is predominant among wild rodents.^[35] Another study in 1996 reported 40 strains.^[36] Genetic methods have revealed even greater complexity than had been previously described (for example, Gilliam is further divided into Gilliam and JG types). Infection with one serotype does not confer immunity to other serotypes (no crossimmunity). Repeated infection in the same individual is, therefore, possible, making vaccine design a bigger problem.^[37]^[38]

Antigenic variation

O. tsutsugamushi has four major surface-membrane proteins (antigens) having molecular weights 22 kDa, 47 kDa, 56 kDa and 110 kDa. The 56-kDa protein is the most important because it is not produced by any other bacteria, and is responsible for making genetic diversity.^[39] It accounts for about 10–15% of the total cell protein. Clinical tests easily recognize the protein, but the 22-kDa, 47-kDa or 110-kDa antigens are not normally detected. The antigenic variation of different strains are due to this protein.^[40] 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 diffrent strains, and its gene is about 1,550 base pairs long. It contains four hypervariable regions, indicating a high level of genetic diversity.^[36]

Disease

O. tsutsugamushi causes scrub typhus, which is a complex and dangerous infection. Infection starts when chiggers bite on the skin for feeding. The bacterium multiplies at the site of feeding (inoculation) and causes tissue damage (necrosis). Necrosis progresses to inflammation of the blood vessels called vasculitis. This in turn causes inflammation of the lymph nodes, called lymphadenopathy. Within a few days, vasculitis extends to various organs includingliver, brain, kidney, meninges and the lung.^[41] The disease is responsible for nearly a quarter of all the febrile (high fever) illness in endemic areas. Mortality in severe case or with improper treatment or misdiagnosis may be as high as 30-70%.^[42] About 6% of infected people die untreated, and 1.4% of the patients die even with medical treatment. Moreover, death rate can be as high as 13% where medical treatment is not properly handled.^[43] In cases of misdiagnosis and failure of treatment, systemic complications rapidly develop including acute respiratory distress syndrome, acute kidney failure, encephalitis, gastrointestinal bleeding, hepatitis, meningitis, myocarditis, pancreatitis, pneumonia, septic shock, thyroiditis, and multi-organ dysfunctions.^[44] Harmful symptoms involving multiple organ failure and neurological impairment are difficult to treat, and can be lifelong debilitation or directly fatal.^[44] The central nervous system is often affected and result in various complications including cerebellitis, cranial nerve palsies, meningoencephalitis, plexopathy, transverse myelitis, neuroleptic malignant syndrome, and Guillan-Barré syndrome.^[45] Death rates due to complications can be up to 14% in brain infections, and 24% with multiple organ failure.^[43] It is the major cause of acute encephalitis syndrome in India, where viral infection Japanese encephalitis has been regarded as the main factor.^[46]

Epidemiology

The World Health Organization stated that

“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.”^[47]

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 entire region is popularly called the Tsutsugamushi Triangle).^[41] However, it has spread to Africa, Europe and South America.^[48] 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 endemic Asia-Pacific region. In the absence of proper medical care, the case fatality rate can go beyond 30% to as high as 70% in some areas.^[29] 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.^[49] 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.^[43]

Treatment

O. tsutsugamushi infection can be treated with antibiotics such as azithromycin, chloramphenicol, doxycycline, rifampicin, roxithromycin, and tetracyclin. But the bacterium is innately resistant to all β-lactam antibiotics (for example, penicillin) because it lacks a classical peptidoglycan cell wall.^[50] Doxycycline is the most commonly used and is considered as the drug of choice because of its 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.^[51] A randomized controlled trial and systematic review showed that azithromycin is the safest medication.^[52]^[53]

Diagnosis

Symptom

File:Scrub typhus eschar.tif

Eschar due to O. tsutsugamushi infection on the shoulder (a, b) of a female and on the penis (c, d) of a male.

The main symptom of O. tsutsugamushi infection is high (febrile) fever; however, the symptom is not unique and belongs to a group of acute undifferentiated fever, which includes those of malaria, leptospirosis, enteric fever, murine typhus, chikungunya and dengue.^[54]^[55] This makes precise clinical diagnosis difficult, and 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 to 21 days.^[41] A useful diagnosis is the presence of an inflamed scar called eschar—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.^[56] 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.^[57] However, eschar is not specific to scrub typhus, as other rickettsial diseases such as Rocky Mountain spotted fever,^[58] Brazilian spotted fever,^[59] and Indian tick typhus.^[60]^[61] Using DNA analysis by advanced polymerase chain reaction, different rickettsial infection can be identified from eschars.^[62]^[63]

Blood test

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.^[28]^[22] IFA is regarded as the gold standard test, as it gives reliable result. However, it is not more expensive and also not specific for different rickettsial bacteria.^[64] 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.^[65] But they are highly sophisticated and expensive techniques.

Vaccine

No licensed O. tsutsugamushi vaccines are currently available. The first vaccines were developed in the late 1940s, but they failed in the clinical trials.^[66]^[67] Considered an ideal target, the unique 56-kDa protein itself is highly variable. 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 locality, because of antigenic variation. This complexity makes it difficult to produce a useful vaccine.^[68] A vaccine targeting the 47-kDa outer membrane protein (OMP) is a promising candidate with experimental success in mice against Boryong strain.^[69]

Immunity

There is no complete immunity to O. tsutsugamushi infection. Enormous antigenic variation among O. tsutsugamushi strains makes the immune system unable to recognise them, and immunity to one strain does not confer immunity to another. An infected individual may develop a short-term immunity but that dissappears after a few month.^[68] An immunisation experiment was done in 1950 in which 16 volunteers still developed the infection after 11–25 months of primary infection.^[70] 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).^[71]

References

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