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{{Short description|Species of bacterium}}
{{Taxobox
| image = Orientia tsutsugamushi.JPG
| image_caption = ''Orientia tsutsugamushi''
| domain = [[Bacteria]]
| phylum = [[Pseudomonadota]]
| classis = [[Alphaproteobacteria]]
| ordo = [[Rickettsiales]]
| familia = [[Rickettsiaceae]]
| genus = ''[[Orientia]]''
| species = ''O. tsutsugamushi''
| binomial = ''Orientia tsutsugamushi''
| binomial_authority = (Hayashi, 1920) (Ogata, 1929) Tamura ''et al.'', 1995
}}

'''''Orientia tsutsugamushi''''' (from [[Japanese (language)|Japanese]] ''tsutsuga'' meaning "illness", and ''mushi'' meaning "insect") is a [[mite]]-borne [[bacterium]] belonging to the family [[Rickettsiaceae]] and is responsible for a disease called [[scrub typhus]] in humans.<ref name="salje">{{cite journal |last1=Salje |first1=J. |last2=Kline |first2=K.A. |title=''Orientia tsutsugamushi'': A neglected but fascinating obligate intracellular bacterial pathogen |journal=PLOS Pathogens |date=2017 |volume=13 |issue=12 |pages=e1006657 |doi=10.1371/journal.ppat.1006657 |pmid=29216334 |pmc=5720522 |doi-access=free }}</ref> It is a natural and an [[Obligate parasite|obligate]] [[intracellular parasite]] of mites belonging to the family [[Trombiculidae]].<ref name="pmid14501995">{{cite journal |last1=Watt |first1=G. |last2=Parola |first2=P. |title=Scrub typhus and tropical rickettsioses |journal=Current Opinion in Infectious Diseases |date=2003 |volume=16 |issue=5 |pages=429–436 |doi=10.1097/00001432-200310000-00009 |pmid=14501995 |s2cid=24087729 }}</ref><ref name="Kelly2009">{{cite journal |last1=Kelly |first1=D.J. |last2=Fuerst |first2=P.A. |last3=Ching |first3=W.M. |last4=Richards |first4=A.L. |title=Scrub typhus: the geographic distribution of phenotypic and genotypic variants of ''Orientia tsutsugamushi'' |journal=Clinical Infectious Diseases |date=2009 |volume=48 Suppl |issue=Suppl |pages=S203–S230 |doi=10.1086/596576 |pmid=19220144|doi-access=free }}</ref> With a genome of only 2.0–2.7 Mb, it has the most [[Repeated sequence (DNA)|repeated DNA sequences]] among bacterial genomes sequenced so far. The disease, scrub typhus, occurs when infected mite larvae accidentally bite humans. This infection can prove fatal if prompt [[doxycycline]] therapy is not  started.

''Orientia 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 first described it in 1920, giving the name ''Theileria tsutsugamushi''. Owing to its unique properties, it was renamed ''Orientia tsutsugamushi'' in 1995. Unlike other [[Gram-negative]] [[bacteria]], it is not easily stained with [[Gram stain]], as 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.<ref>{{cite journal |last1=Yamamoto |first1=S. |last2=Kawabata |first2=N. |last3=Tamura |first3=A. |last4=Urakami |first4=H. |last5=Ohashi |first5=N. |last6=Murata |first6=M. |last7=Yoshida |first7=Y. |last8=Kawamura A |first8=Jr. |title=Immunological properties of ''Rickettsia tsutsugamushi'', Kawasaki strain, isolated from a patient in Kyushu |journal=Microbiology and Immunology |date=1986 |volume=30 |issue=7 |pages=611–620 |pmid=3095612 |doi=10.1111/j.1348-0421.1986.tb02988.x|s2cid=2968436 }}</ref> Within each strain, enormous variability further exists.

''Orientia 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 [[Parasitism|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|immunofluorescence assays]], and [[polymerase chain reaction]]. There is no vaccine for the infection.

==History==
The earliest record of ''O. tsutsugamushi'' infection was in the 3rd century (313 C.E.) in China.<ref>{{cite journal |last1=Fan |first1=M.Y. |last2=Walker |first2=D.H. |last3=Yu |first3=S.R. |last4=Liu |first4=Q.H. |title=Epidemiology and ecology of rickettsial diseases in the People's Republic of China |journal=Reviews of Infectious Diseases |date=1987 |volume=9 |issue=4 |pages=823–840 |doi=10.1093/clinids/9.4.823 |pmid=3326129}}</ref> 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 illness, 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 infection along the banks of the upper tributaries of [[Shinano River]].<ref>{{cite book |last1=Kawamura |first1=R. |title=Studies on tsutsugamushi disease (Japanese Blood Fever) |date=1926 |publisher=Spokesman Printing Company |location=Cincinnati, OH (USA) |page=2}}</ref> The first report to the Western world was made by Theobald Adrian Palm, a physician of the [[EMMS International|Edinburgh Medical Missionary Society]] at Niigata in 1878. Describing his first-hand experience, Palm wrote:
{{Quote|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.<ref>{{cite journal |last1=Palm |first1=T.A. |title=Some account of a disease called "shima-mushi," or "island-insect disease," by the natives of Japan; peculiar, it is believed, to that country, and hitherto not described |journal=Edinburgh Medical Journal |date=1878 |volume=24 |issue=2 |pages=128–132 |pmid=29640208 |pmc=5317505}}</ref>}}

The aetiology of the disease was unknown until the early 20th century. In 1908, a mite theory of the transmission of tsutsugamushi disease was postulated by Taichi Kitashima and Mikinosuke Miyajima.<ref name=miyajima17>{{cite journal|last1=Miyajima|first1=M.|last2=Okumura|first2=T.|title=On the life cycle of the "Akamushi" carrier of Nippon river fever|journal=Kitasato Archives of Experimental Medicine|date=1917|volume=1|issue=1|pages=1–14}}</ref> 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.<ref>{{cite journal|last1=Hirst|first1=S.|title=On the Tsutsugamushi (''Microtrombidium akamushi'', Brumpt), carrier of Japanese river fever|journal=Journal of Economic Biology|date=1915|volume=10|issue=4|pages=79–82}}</ref> 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. They also asserted that only the larvae bites mammals, and are thus the only carriers of the parasites.<ref>{{cite journal|last1=Nagayo|first1=M.|title=On the nymph and prosopon of the tsutsugamushi, ''Leptotrombidium akamushi, N. Sp.'' (''Trombidium akamushi'' Brumpt), carrier of tsutsugamushi disease|journal=Journal of Experimental Medicine|date=1917|volume=25|issue=2|pages=255–272|doi=10.1084/jem.25.2.255|pmid=19868085|pmc=2125768}}</ref> But then, the actual infectious agent was not known, and it was generally attributed to either a virus or a protozoan.<ref name="lalchhandama18">{{cite journal|last1=Lalchhandama|first1=K.|title=The saga of scrub typhus with a note on the outbreaks in Mizoram|journal=Science Vision|date=2018|volume=18|issue=2|pages=50–57|url=https://www.sciencevision.org/issue/4/article/11|doi=10.33493/scivis.18.02.01|doi-access=free}}</ref>

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 ''[[Piroplasmida|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''."<ref>{{cite journal|last1=Hayashi|first1=N.|title=Etiology of tsutsugamushi disease|journal=The Journal of Parasitology|date=1920|volume=7|issue=2|pages=52–68|doi=10.2307/3270957|jstor=3270957|url=https://www.biodiversitylibrary.org/part/316315}}</ref> Discovering the similarities with the bacterium ''R. prowazekii'', Mataro Nagayo and colleagues gave a new classification with the name ''Rickettsia orientalis'' in 1930.<ref>{{cite journal|last1=Nagayo|first1=M.|last2=Tamiya|first2=T.|last3=Mitamura|first3=T.|last4=Sato|first4=K.|title=On the virus of tsutsugamushi disease and its demonstration by a new method|journal=Jikken Igaku Zasshi (Japanese Journal of Experimental Medicine)|date=1930|volume=8|issue=4|pages=309–318}}</ref><ref>{{cite journal|last1=Nagayo|first1=M.|last2=Tamiya|first2=T.|last3=Mitamura|first3=T.|last4=Sato|first4=K.|title=Sur le virus de la maladie de Tsutsugamushi [On the virus of tsutsugamushi]|journal=Comptes Rendus des Séances de la Société de Biologie|date=1930|volume=104|pages=637–641}}</ref> (''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.<ref>{{cite journal |last1=da Rocha Lima |first1=H. |title=Untersuchungen über fleckfleber [Researches on typhus] |journal=Münchener medizinische Wochenschrift |date=1916 |volume=63 |issue=39 |pages=1381–1384}}</ref>)

The taxonomic confusion worsened. In 1931, Norio Ogata gave the name ''Rickettsia tsutsugamushi'',<ref>{{cite journal|last1=Ogata|first1=N.|title= Aetiologie der Tsutsugamushi-krankheit: ''Rickettsia tsutsugamushi'' [Aetiology of the tsutsugamushi disease: ''Rickettsia tsutsugamushi'' |journal=Zentralblatt für Bakteriologie, Parasitenkunde, Infektionskrankheiten und Hygiene|date=1931|volume=122|pages=249–253}}</ref> while Rinya Kawamüra and Yoso Imagawa independently introduced the name ''Rickettsia akamushi''.<ref>{{cite journal|last1=Kawamüra|first1=R.|last2=Imagawa|first2=Y.|title=Ueber die Proliferation der pathogenen ''Rickettsia'' im tierischen organismus bei der tsutsugamushi-krankheit [The multiplication of the ''Rickettsia'' pathogen of tsutsugamushi disease in animals]|journal=Transactions of the Japanese Society of Pathology|date=1931|volume=21|pages=455–461}}</ref> 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 parasites during feeding.<ref>{{cite journal|last1=Kawamüra|first1=R.|last2=Imagawa|first2=Y.|title=Die feststellung des erregers bei der tsutsugamushikrankheit [Confirmation of the infective agent in tsutsugamushi disease]|journal=Zentralblatt für Bakteriologie, Parasitenkunde, Infektionskrankheiten und Hygiene|date=1931|volume=122|issue=4/5|pages=253–261}}</ref>

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 a separate genus, and proposed the name ''Orientia tsutsugamushi''.<ref name=tamura91>{{cite journal |last1=Tamura |first1=A. |last2=Urakami |first2=H. |last3=Ohashi |first3=N. |title=A comparative view of ''Rickettsia tsutsugamushi'' and the other groups of Rickettsiae |journal=European Journal of Epidemiology |date=1991 |volume=7 |issue=3 |pages=259–269 |doi=10.1007/BF00145675 |pmid=1909244|s2cid=12298540 }}</ref> Finally, in 1995, they made a new classification based on the morphological and biochemical properties, formally creating the new name ''O. tsutsugamushi''.<ref name=tamura95/>

==Biology==
[[File:O. tsutsugamushi in U937 cells.tif|thumb|''O. tsutsugamushi'' in human (U937) cells.]]
''Orientia tsutsugamushi'' is a Gram-negative bacterium and is a permanent (obligate) parasite in mites. Within a single host cell, ''O. tsutsugamushi'' rapidly divides into many individuals as shown in '''Figure 1'''. A unicellular organism, it is oval shaped and measures 0.5 to 0.8&nbsp;μm wide and 1.2 to 3.0&nbsp;μm long. Due to similarity, it was previously classified in the genus ''[[Rickettsia]]'' among other bacteria, but later assigned a separate genus, ''Orientia'',<ref name=tamura95>{{cite journal|last1=Tamura|first1=A.|last2=Ohashi|first2=N.|last3=Urakami|first3=H.|last4=Miyamura|first4=S.|title=Classification of ''Rickettsia tsutsugamushi'' in a new genus, ''Orientia'' gen. nov., as ''Orientia tsutsugamushi'' comb. nov.|journal=International Journal of Systematic Bacteriology|date=1995|volume=45|issue=3|pages=589–591|doi=10.1099/00207713-45-3-589|pmid=8590688|doi-access=free}}</ref> which it shares (as of 2010) only with ''Candidatus Orientia chuto''.<ref>{{cite journal|last1=Izzard|first1=L|title=Isolation of a novel ''Orientia'' species (''O. chuto'' sp. nov.) from a patient infected in Dubai|journal=Journal of Clinical Microbiology |date=2010|volume=48 |issue=12|pages=4404–4409|doi=10.1128/JCM.01526-10 |pmid=20926708|pmc=3008486}}</ref> It is broader but shorter than other rickettsial bacteria, which are rod shaped and on average measure 0.25 to 0.3&nbsp;μm wide and 0.8 to 1&nbsp;μm long.<ref>{{cite journal |last1=Sunyakumthorn |first1=P. |last2=Bourchookarn |first2=A. |last3=Pornwiroon |first3=W. |last4=David |first4=C. |last5=Barker |first5=S. A. |last6=Macaluso |first6=K. R. |title=Characterization and growth of polymorphic ''Rickettsia felis'' in a tick cell Line |journal=Applied and Environmental Microbiology |date=2008 |volume=74 |issue=10 |pages=3151–3158 |doi=10.1128/AEM.00025-08 |pmid=18359823 |pmc=2394910|bibcode=2008ApEnM..74.3151S }}</ref> 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 cycle takes 9 to 18 hours.<ref>{{cite journal |last1=Moree |first1=M.F. |last2=Hanson |first2=B. |title=Growth characteristics and proteins of plaque-purified strains of ''Rickettsia tsutsugamushi'' |journal=Infection and Immunity |date=1992 |volume=60 |issue=8 |pages=3405–3415 |doi=10.1128/IAI.60.8.3405-3415.1992 |pmid=1379212 |pmc=257328}}</ref>

The structure of ''O. tsutsugamushi'' (revealed by [[transmission electron microscopy]]) is shown in '''Figure 2'''. The bacterium is enclosed by a [[cell wall]] on the outside and cell membrane on the inside. The cell covering takes up stains such as [[Giemsa stain|Giemsa]] and [[Gimenez stain]]s. Although its cell wall has a classic bacterial double layer, its outer leaflet is much thicker than the inner one, which is just the opposite in ''Rickettsia'' species.<ref>{{cite journal |last1=Silverman |first1=D.J. |last2=Wisseman |first2=C.L. Jr. |title=Comparative ultrastructural study on the cell envelopes of ''Rickettsia prowazekii'', ''Rickettsia rickettsii'', and ''Rickettsia tsutsugamushi'' |journal=Infection and Immunity |date=1978 |volume=21 |issue=3 |pages=1020–1023 |doi=10.1128/IAI.21.3.1020-1023.1978 |pmid=101465 |pmc=422098}}</ref> A capsule layer that forms a spherical halo in other bacteria is missing. The cell wall is less rigid due to the absence of peptidoglycan, which is otherwise characteristic of the rigid cell walls of other bacteria. Classic bacterial lipophosphoglycans such as [[muramic acid]], [[glucosamine]], hydroxy fatty acids, [[heptose]], and 2-keto-3-deoxyoctonic acid are also absent in the cell wall. Due to the absence of [[peptidoglycan]], the bacterium is naturally resistant to all [[beta-lactam|β-lactam]] antibiotics (such as [[penicillin]]), to which ''Rickettsia'' species are normally sensitive to.<ref name=tamura87>{{cite journal |last1=Amano |first1=K. |last2=Tamura |first2=A. |last3=Ohashi |first3=N. |last4=Urakami |first4=H. |last5=Kaya |first5=S. |last6=Fukushi |first6=K. |title=Deficiency of peptidoglycan and lipopolysaccharide components in ''Rickettsia tsutsugamushi'' |journal=Infection and Immunity |date=1987 |volume=55 |issue=9 |pages=2290–2292 |doi=10.1128/IAI.55.9.2290-2292.1987 |pmid=3114150 |pmc=260693}}</ref> Its genome totally lacks the genes for lipophosphoglycan synthesis, but does contain some for those of peptidoglycan. Important genes essential for peptidoglycan synthesis such as ''alr'', ''dapF'' and ''PBP1'' are missing: ''alr'' encodes an enzyme L-alanine racemase, which converts L-alanine to D-alanine in the first step of peptidoglycan synthesis pathway; ''dapF'' encodes diaminopimelate epimerase, which convert LL-2,6-diaminoheptanedioate (L,L-DAP) to meso-diaminoheptanedioate (meso-DAP); and ''PBP1'' encodes penicillin-binding protein-1 (PBP1), which converts periplasmic lipid II to peptidoglycan. Thus, the bacterium cannot synthesise a typical peptidoglycan cell wall, and instead makes a peptidoglycan-like structure on its surface.<ref>{{cite journal |last1=Atwal |first1=S. |last2=Giengkam |first2=S. |last3=Chaemchuen |first3=S. |last4=Dorling |first4=J. |last5=Kosaisawe |first5=N. |last6=VanNieuwenhze |first6=M. |last7=Sampattavanich |first7=S. |last8=Schumann |first8=P. |last9=Salje |first9=J. |title=Evidence for a peptidoglycan-like structure in ''Orientia tsutsugamushi'' |journal=Molecular Microbiology |date=2017 |volume=105 |issue=3 |pages=440–452 |doi=10.1111/mmi.13709 |pmid=28513097|pmc=5523937}}</ref> The cell membrane is also chemically different in its protein composition, and this difference gives rise to strain variations within the species itself.<ref name="lalchhandama">{{cite journal|last1=Lalchhandama|first1=K. |title=Rickettsiosis as a critical emerging infectious disease in India|journal=Science Vision|date=2017|volume=17|issue=4|pages=250–259 |url=https://www.sciencevision.org/issue/2/article/46|doi=10.33493/scivis.17.04.09|doi-access=free}}</ref> The cytoplasm is clear and shows distinct DNA and ribosomes.

[[File:O. tsutsugamushi genomes.tif|thumb|Genomes of ''O. tsutsugamushi'' strains. From outermost to innermost ring of each genome: [[Repeated sequence (DNA)|repetitive regions]] in purple, [[Housekeeping gene|core genes]] in green, repeat genes in red and [[pseudogene]]s in blue. The innermost line graph shows [[GC-content]] (1000bp windows) with above-median region in green, and below-median regions in red.]]
The bacterium is highly virulent, such that its isolation and cell culture are done only in a laboratory facility with [[biosafety level| biosafety level 3]]. Unlike other bacteria which can easily grow on different culture media, rickettsiales can be cultured only in living cells. ''O. tsutsugamushi'' specifically can be grown only in the yolk sacs of developing chicken embryos and in cultured cell lines such as [[HeLa]], [[Baby hamster kidney cell|BHK]], [[Vero cell|Vero]], and [[Enteroendocrine cell|L929]].<ref name=koh>{{cite journal |last1=Koh |first1=G.C. |last2=Maude |first2=R.J. |last3=Paris |first3=D.H. |last4=Newton |first4=P.N. |last5=Blacksell |first5=S.D. |title=Diagnosis of scrub typhus |journal=The American Journal of Tropical Medicine and Hygiene |date=2010 |volume=82 |issue=3 |pages=368–370 |doi=10.4269/ajtmh.2010.09-0233 |pmid=20207857 |pmc=2829893}}</ref> In contrast to ''Rickettsia'' species which reside in the nucleus of the host cell, ''O. tsutsugamushi'' mostly grows within the cytoplasm of the host cell.<ref name=tamura91/> Genetically, it differs from other ''Rickettsia'' by only 9%.<ref>{{cite journal |last1=Ohashi |first1=N. |last2=Fukuhara |first2=M. |last3=Shimada |first3=M. |last4=Tamura |first4=A. |title=Phylogenetic position of ''Rickettsia tsutsugamushi'' and the relationship among its antigenic variants by analyses of 16S rRNA gene sequences |journal=FEMS Microbiology Letters |date=1995 |volume=125 |issue=2–3 |pages=299–304 |doi=10.1111/j.1574-6968.1995.tb07372.x |pmid=7875578|doi-access=free }}</ref> Even though adaptation to [[Intracellular parasite#Obligate|obligate intracellular parasitism]] among bacteria generally results in a reduced genome, it has a genome size of about 2.0–2.7 [[Base pair|Mb]] depending on the strains ('''Figure 3'''), which is comparatively larger than those of other rickettsiales – two times larger than that of ''[[Rickettsia prowazekii]]'',<ref>{{cite journal |last1=Bishop-Lilly |first1=K.A. |last2=Ge |first2=H. |last3=Butani |first3=A. |last4=Osborne |first4=B. |last5=Verratti |first5=K. |last6=Mokashi |first6=V. |last7=Nagarajan |first7=N. |last8=Pop |first8=M. |last9=Read |first9=T.D. |last10=Richards |first10=A.L. |title=Genome sequencing of four strains of ''Rickettsia prowazekii'', the causative agent of epidemic typhus, including one flying squirrel isolate |journal=Genome Announcements |date=2013 |volume=1 |issue=3 |pages=e00399-13 |doi=10.1128/genomeA.00399-13 |pmid=23814035 |pmc=3695431}}</ref> the most well-known member. The entire genome is distributed in a single circular chromosome. Whole genome sequences are available only for Ikeda and Boryong strains, both from the Republic of Korea. The genome of the Ikeda strain is 2,008,987 base pairs (bp) long, and contains 1,967 protein-coding genes.<ref>{{cite journal |last1=Nakayama |first1=K. |last2=Yamashita |first2=A. |last3=Kurokawa |first3=K. |last4=Morimoto |first4=T. |last5=Ogawa |first5=M. |last6=Fukuhara |first6=M. |last7=Urakami |first7=H. |last8=Ohnishi |first8=M. |last9=Uchiyama |first9=I. |last10=Ogura |first10=Y. |last11=Ooka |first11=T. |last12=Oshima |first12=K. |last13=Tamura |first13=A. |last14=Hattori |first14=M. |last15=Hayashi |first15=T. |title=The whole-genome sequencing of the obligate intracellular bacterium ''Orientia tsutsugamushi'' revealed massive gene amplification during reductive genome evolution |journal=DNA Research |date=2008 |volume=15 |issue=4 |pages=185–199 |doi=10.1093/dnares/dsn011 |pmid=18508905 |pmc=2575882}}</ref> The Boryong strain is larger with 2,127,051 bp and 2,179 protein-coding genes.<ref name="Cho07">{{cite journal |last1=Cho |first1=N.-H. |last2=Kim |first2=H.-R. |last3=Lee |first3=J.-H. |last4=Kim |first4=S.-Y. |last5=Kim |first5=J. |last6=Cha |first6=S. |last7=Kim |first7=S.-Y. |last8=Darby |first8=A. C. |last9=Fuxelius |first9=H.-H. |last10=Yin |first10=J. |last11=Kim |first11=J. H. |last12=Kim |first12=J. |last13=Lee |first13=S. J. |last14=Koh |first14=Y.-S. |last15=Jang |first15=W.-J. |last16=Park |first16=K.-H. |last17=Andersson |first17=S. G. E. |last18=Choi |first18=M.-S. |last19=Kim |first19=I.-S. |title=The ''Orientia tsutsugamushi'' genome reveals massive proliferation of conjugative Type IV secretion system and host-cell interaction genes |journal=Proceedings of the National Academy of Sciences |date=2007 |volume=104 |issue=19 |pages=7981–7986 |doi=10.1073/pnas.0611553104 |pmid=17483455 |pmc=1876558|bibcode=2007PNAS..104.7981C |doi-access=free }}</ref>

Genome comparison shows only 657 core genes among the different strains.<ref name=batty18>{{cite journal |last1=Batty |first1=E.M. |last2=Chaemchuen |first2=S. |last3=Blacksell |first3=S. |last4=Richards |first4=A.L. |last5=Paris |first5=D. |last6=Bowden |first6=R. |last7=Chan |first7=C. |last8=Lachumanan |first8=R. |last9=Day |first9=N. |last10=Donnelly |first10=P. |last11=Chen |first11=S. |last12=Salje |first12=J. |last13=Reck |first13=J. |title=Long-read whole genome sequencing and comparative analysis of six strains of the human pathogen ''Orientia tsutsugamushi'' |journal=PLOS Neglected Tropical Diseases |date=2018 |volume=12 |issue=6 |pages=e0006566 |doi=10.1371/journal.pntd.0006566 |pmid=29874223 |pmc=6005640 |doi-access=free }}</ref> With about 42-47% of repetitive sequences, ''O. tsutsugamushi'' has the most highly repeated bacterial genome sequenced as of 2013.<ref name=viswanathan13>{{cite journal|last1=Viswanathan|first1=S.|last2=Muthu|first2=V.|last3=Iqbal|first3=N.|last4=Remalayam|first4=B.|last5=George|first5=T|title=Scrub typhus meningitis in South India—a retrospective study|journal=PLOS ONE|date=2013|volume=8|issue=6|pages=e66595|doi=10.1371/journal.pone.0066595|pmid=23799119|pmc=3682970|bibcode=2013PLoSO...866595V|doi-access=free}}</ref> The repeated DNA sequence includes short [[Repeated sequence (DNA)|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|Integrative and Conjugative Element (ICE)]] called the rickettsial amplified genetic element (RAGE).<ref name="Cho07"/> 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.<ref name="salje"/>

===Life cycle and transmission===
[[File:Trombicula-larva-stylostome.jpg|thumb|Chigger with its stylostome (arrowhead), the feeding apparatus.]]
''Orientia tsutsugamushi'' is naturally transmitted in the mite population belonging to the genus ''[[Leptotrombidium]]''. It can be transmitted by a female to its eggs through the process called transovarial transmission, and from the eggs to larvae and adults through the process of transstadial 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 of the bacterium. In fact, in humans the transmission is stopped, and the bacterium meets a dead end.<ref name="lalchhandama"/> However, uninfected mites can acquire the infection from infected rodents.<ref>{{cite journal |last1=Takhampunya |first1=R. |last2=Korkusol |first2=A. |last3=Promsathaporn |first3=S. |last4=Tippayachai |first4=B. |last5=Leepitakrat |first5=S. |last6=Richards |first6=A.L. |last7=Davidson |first7=S.A. |last8=Small |first8=P.L.C. |title=Heterogeneity of ''Orientia tsutsugamushi'' genotypes in field-collected trombiculid mites from wild-caught small mammals in Thailand |journal=PLOS Neglected Tropical Diseases |date=2018 |volume=12 |issue=7 |pages=e0006632 |doi=10.1371/journal.pntd.0006632 |pmid=30011267 |pmc=6062101 |doi-access=free }}</ref>

In rodent and human infections, ''[[Leptotrombidium deliense]]'' is the most common 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.<ref name="Kelly2009"/> In parts of India, a different mite species, ''Schoengastiella ligula'' is also a major vector.<ref>{{cite journal |last1=Tilak |first1=R. |last2=Wankhade |first2=U. |last3=Kunwar |first3=R. |last4=Tilak |first4=V.W. |title=Emergence of ''Schoengastiella ligula'' as the vector of scrub typhus outbreak in Darjeeling: Has ''Leptotrombidium deliense'' been replaced? |journal=Indian Journal of Public Health |date=2011 |volume=55 |issue=2 |pages=92–99 |doi=10.4103/0019-557X.85239 |pmid=21941043|doi-access=free }}</ref> The life cycle of mites consists of egg, prelarva, larva, protonymph, deutonymph, tritonymph, and adult. The larvae, commonly referred to as chiggers ('''Figure 4'''), 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 transmit the infection. Wild rats of the genus ''[[Rattus]]'' are the principal natural hosts of the chiggers.<ref name="luce18">{{cite journal|last1=Luce-Fedrow|first1=A.|last2=Lehman|first2=M.|last3=Kelly|first3=D.|last4=Mullins|first4=K.|last5=Maina|first5=A.|last6=Stewart|first6=R.|last7=Ge|first7=H.|last8=John|first8=H.|last9=Jiang|first9=J.|last10=Richards|first10=Allen|title=A review of scrub typhus (''Orientia tsutsugamushi'' and related organisms): then, now, and tomorrow|journal=Tropical Medicine and Infectious Disease|date=2018|volume=3|issue=1|page=8|doi=10.3390/tropicalmed3010008|pmid=30274407|pmc=6136631|doi-access=free}}</ref> Chiggers feed only once on a mammalian host. The feeding usually takes 2 to 4 days. In contrast to most parasites, they do not feed on blood, but instead on the body fluid through the hair follicles or skin pores. In the process of feeding, they create a [[stylostome]], which is a tube formed by solidified saliva. 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.<ref name=xu17>{{cite journal|last1=Xu|first1=G.|last2=Walker|first2=D.H.|last3=Jupiter|first3=D.|last4=Melby|first4=P.C.|last5=Arcari|first5=C.M.|last6=Day|first6=N.P.|title=A review of the global epidemiology of scrub typhus|journal=PLOS Neglected Tropical Diseases|date=2017|volume=11|issue=11|pages=e0006062 |pmc=5687757 |pmid=29099844 |doi=10.1371/journal.pntd.0006062 |doi-access=free }}</ref>

===Cellular invasion===
[[File:Orientia cell invasion.png|thumb|Mechanism of cell invasion by ''O. tsutsugamushi''.]]
''Orientia tsutsugamushi'' initially attacks the [[myelocyte]]s (young white blood cells) in the area of inoculation, and then the [[Endothelium|endothelial cells]] lining the [[Circulatory system|vasculature]]. The process of cellular invasion is shown in '''Figure 5'''. In the blood circulation, it targets professional phagocytes ("cell eaters", white blood cells) such as [[dendritic cell]]s and [[macrophages]] in all organs as 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 type specific protein 56 (or type specific antigen, TSA56) and surface cell antigens (ScaA and ScaC, which are membrane transporter proteins).<ref>{{cite journal |last1=Ge |first1=Y. |last2=Rikihisa |first2=Y. |title=Subversion of host cell signaling by ''Orientia tsutsugamushi'' |journal=Microbes and Infection |date=2011 |volume=13 |issue=7 |pages=638–648 |doi=10.1016/j.micinf.2011.03.003 |pmid=21458586|doi-access=free }}</ref><ref name=ha15>{{cite journal |last1=Ha |first1=N.Y. |last2=Sharma |first2=P. |last3=Kim |first3=G. |last4=Kim |first4=Y. |last5=Min |first5=C.K. |last6=Choi |first6=M.S. |last7=Kim |first7=I.S. |last8=Cho |first8=N.H. |title=Immunization with an autotransporter protein of ''Orientia tsutsugamushi'' provides protective immunity against scrub typhus |journal=PLOS Neglected Tropical Diseases |date=2015 |volume=9 |issue=3 |pages=e0003585 |doi=10.1371/journal.pntd.0003585 |pmid=25768004 |pmc=4359152 |doi-access=free }}</ref> These proteins interact with the host [[fibronectin]] to induce [[phagocytosis]] (the process of ingesting the bacterium). The ability to actually enter the host cell depends on [[integrin]]-mediated signaling and reorganisation of the [[actin]] cytoskeleton.<ref>{{cite journal |last1=Cho |first1=B. A. |last2=Cho |first2=N. H. |last3=Seong |first3=S. Y. |last4=Choi |first4=M. S. |last5=Kim |first5=I. S. |title=Intracellular invasion by ''Orientia tsutsugamushi'' is mediated by integrin signaling and actin cytoskeleton rearrangements |journal=Infection and Immunity |date=2010 |volume=78 |issue=5 |pages=1915–1923 |doi=10.1128/IAI.01316-09 |pmid=20160019 |pmc=2863532}}</ref>

''Orientia 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|clathrin-coated vesicle]] by which it gets transported into the cytoplasm. Inside the cytoplasm, it makes an exit from the vesicle (now known as an [[endosome]]) before the endosome is destroyed (in the process of cell-eating called [[autophagy]]) by the [[lysosome]]s.<ref>{{cite journal |last1=Ko |first1=Y. |last2=Choi |first2=J.H. |last3=Ha |first3=N.Y |last4=Kim |first4=I.S. |last5=Cho |first5=N.H. |last6=Choi |first6=M.S. |last7=Bäumler |first7=A. J. |title=Active escape of ''Orientia tsutsugamushi'' from cellular autophagy |journal=Infection and Immunity |date=2013 |volume=81 |issue=2 |pages=552–559 |doi=10.1128/IAI.00861-12 |pmid=23230293 |pmc=3553808}}</ref> 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 transport|intracellular trafficking or transport]]), ''O. tsutsugamushi'' is unusual in using [[microtubule]]-mediated processes similar to those employed by viruses such as [[Adenoviridae|adenoviruses]] and [[herpes simplex virus]]es. Further, the escape ([[exocytosis]]) from an infected host cell is also unusual. It forms another vesicle using the host cell membrane, gives rise to a 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.<ref>{{cite journal |last1=Kim |first1=M.J. |last2=Kim |first2=M.K. |last3=Kang |first3=J.S. |title=Involvement of lipid rafts in the budding-like exit of ''Orientia tsutsugamushi'' |journal=Microbial Pathogenesis |date=2013 |volume=63 |pages=37–43 |doi=10.1016/j.micpath.2013.06.002 |pmid=23791848}}</ref> However, the process of budding and importance of the membrane-bound bacterium are not yet understood.

===Strains===
''Orientia tsutsugamushi'' is a diverse species of bacteria. Ida A. Bengtson of the [[United States Public Health Service]] was the first to note the existence of different strains using antigen-antibody interaction ([[complement fixation test]]) in 1944.<ref>{{cite journal |last1=Bengston |first1=I.A. |title=Apparent serological heterogeneity among strains of Tsutsugamushi disease (scrub typhus) |journal=Public Health Reports |date=1945 |volume=60 |issue=50 |pages=1483–1488 |doi=10.2307/4585496 |jstor=4585496 |pmid=21004496|s2cid=41472189 }}</ref> She observed that different strains had varying degree of virulence, and that the antibodies in the blood sera of patients cross-react to different strains. By 1946, she established that there were three principal strains (serotypes), namely Karp (from New Guinea), Gilliam (from India) and Seerangay (from British Malaya).<ref>{{cite journal |last1=Bengston |first1=I.A. |title=A serological study of 37 cases of tsutsugamushi disease (scrub typhus) occurring in Burma and the Philippine Islands |journal=Public Health Reports |date=1946 |volume=61 |issue=24 |pages=887–894 |doi=10.2307/4585717 |jstor=4585717 |pmid=20987857}}</ref> Akira Shishido described the Kato strain, in addition to Gilliam and Karp, in Japan in 1958.<ref>{{cite journal |last1=Shishido |first1=A. |last2=Ohtawara |first2=M. |last3=Tateno |first3=S. |last4=Mizuno |first4=S. |last5=Ogura |first5=M. |last6=Kitaoka |first6=M. |title=The nature of immunity against scrub typhus in mice i. the resistance of mice, surviving subcutaneous infection of scrub typhus rickettsia, to intraperitoneal reinfection of the same agent |journal=Japanese Journal of Medical Science and Biology |date=1958 |volume=11 |issue=5 |pages=383–399 |doi=10.7883/yoken1952.11.383|s2cid=87963514 }}</ref> Since then, six basic antigenic strains are recognised, namely Gilliam, Karp, Kato, Shimokoshi, Kawasaki, and Kuroki. Karp is the most abundant strain, accounting for about 50% of all infections.<ref name="Kelly2009"/> In Korea, the major strain is Boryong.<ref>{{cite journal |last1=Jang |first1=M.S. |last2=Neupane |first2=G.P. |last3=Lee |first3=Y.M. |last4=Kim |first4=D.M. |last5=Lee |first5=S.H. |title=Phylogenetic analysis of the 56 kDa protein genes of ''Orientia tsutsugamushi'' in southwest area of Korea |journal=The American Journal of Tropical Medicine and Hygiene |date=2011 |volume=84 |issue=2 |pages=250–254 |doi=10.4269/ajtmh.2011.09-0601 |pmid=21292894 |pmc=3029177}}</ref> As of 2009, more than 20 different strains have been established in humans based on [[antigenic variation]] using serological tests such as complement fixation and immunofluorescence assay.<ref name="Kelly2009"/> 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.<ref>{{cite journal|last1=Yamashita|first1=T.|last2=Kasuya|first2=S.|last3=Noda|first3=N.|last4=Nagano|first4=I.|last5=Kang|first5=J.S.|title=Transmission of ''Rickettsia tsutsugamushi'' strains among humans, wild rodents, and trombiculid mites in an area of Japan in which tsutsugamushi disease is newly endemic|journal=Journal of Clinical Microbiology|date=1994|volume=32|issue=11|pages=2780–2785|doi=10.1128/JCM.32.11.2780-2785.1994|pmid=7852572|pmc=264159}}</ref> Another study in 1996 reported 40 strains.<ref name=ohashi>{{cite journal |last1=Ohashi |first1=N. |last2=Koyama |first2=Y. |last3=Urakami |first3=H. |last4=Fukuhara |first4=M. |last5=Tamura |first5=A. |last6=Kawamori |first6=F. |last7=Yamamoto |first7=S. |last8=Kasuya |first8=S. |last9=Yoshimura |first9=K. |title=Demonstration of antigenic and genotypic variation in ''Orientia tsutsugamushi'' which were isolated in Japan, and their classification into type and subtype |journal=Microbiology and Immunology |date=1996 |volume=40 |issue=9 |pages=627–638 |doi=10.1111/j.1348-0421.1996.tb01120.x |pmid=8908607|s2cid=22112557 |doi-access=free }}</ref> Genetic methods have revealed even greater complexity than had been previously described (for example, Gilliam is further divided into Gilliam and JG types). Due to immunological differences of the serotypes, simultaneous and repeated infection with different strains is possible.<ref>{{cite journal |last1=Bakshi |first1=D. |last2=Singhal |first2=P. |last3=Mahajan |first3=S.K. |last4=Subramaniam |first4=P. |last5=Tuteja |first5=U. |last6=Batra |first6=H.V. |title=Development of a real-time PCR assay for the diagnosis of scrub typhus cases in India and evidence of the prevalence of new genotype of ''O. tsutsugamushi'' |journal=Acta Tropica |date=2007 |volume=104 |issue=1 |pages=63–71 |doi=10.1016/j.actatropica.2007.07.013 |pmid=17870041}}</ref><ref>{{cite journal |last1=Parola |first1=P. |last2=Blacksell |first2=S.D. |last3=Phetsouvanh |first3=R. |last4=Phongmany |first4=S. |last5=Rolain |first5=J.M. |last6=Day |first6=N.P. |last7=Newton |first7=P.N. |last8=Raoult |first8=D. |title=Genotyping of ''Orientia tsutsugamushi'' from humans with scrub typhus, Laos |journal=Emerging Infectious Diseases |date=2008 |volume=14 |issue=9 |pages=1483–1485 |doi=10.3201/eid1409.071259 |pmid=18760027 |pmc=2603112}}</ref>

====Antigenic variation====
''Orientia tsutsugamushi'' has four major surface-membrane proteins ([[antigens]]) having molecular weights 22 kDa, 47 kDa, 56 kDa and 110 kDa. A 56-kDa type specific antigen (TSA56) is the most important because it is not produced by any other bacteria, and is responsible for making the genetic diversity in different strains.<ref>{{cite journal |last1=Tamura |first1=A |last2=Ohashi |first2=N |last3=Urakami |first3=H |last4=Takahashi |first4=K |last5=Oyanagi |first5=M |title=Analysis of polypeptide composition and antigenic components of ''Rickettsia tsutsugamushi'' by polyacrylamide gel electrophoresis and immunoblotting |journal=Infection and Immunity |date=1985 |volume=48 |issue=3 |pages=671–675 |doi=10.1128/IAI.48.3.671-675.1985 |pmid=3922893 |pmc=261225}}</ref> It accounts for about 10–15% of the total cell proteins. The 22-kDa, 47-kDa or 110-kDa antigens are not strain specific so that TSA56 is the main target in sophisticated diagnostic tests such as immunoblotting, ELISA and DNA analysis.<ref>{{cite journal |last1=Stover |first1=CK |last2=Marana |first2=DP |last3=Carter |first3=JM |last4=Roe |first4=BA |last5=Mardis |first5=E |last6=Oaks |first6=EV |title=The 56-kilodalton major protein antigen of ''Rickettsia tsutsugamushi'': molecular cloning and sequence analysis of the sta56 gene and precise identification of a strain-specific epitope |journal=Infection and Immunity |date=1990 |volume=58 |issue=7 |pages=2076–2084 |doi=10.1128/IAI.58.7.2076-2084.1990 |pmid=1694818 |pmc=258779}}</ref> 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 approximately 1,550 base pairs long. Its gene contains four hypervariable regions, indicating that it synthesises many antigenically different proteins.<ref name=ohashi/> There are also 11-kDa and 60-kDa proteins inside the bacterium which are very similar to [[GroES]] and [[GroEL]] of the bacterium ''[[Escherichia coli]]'', but not that of ''Rickettsia'' species.<ref>{{cite journal |last1=Stover |first1=C.K. |last2=Marana |first2=D.P. |last3=Dasch |first3=G.A. |last4=Oaks |first4=E.V. |title=Molecular cloning and sequence analysis of the Sta58 major antigen gene of ''Rickettsia tsutsugamushi'': sequence homology and antigenic comparison of Sta58 to the 60-kilodalton family of stress proteins |journal=Infection and Immunity |date=1990 |volume=58 |issue=5 |pages=1360–1368 |doi=10.1128/IAI.58.5.1360-1368.1990 |pmid=2108930| pmc=258633}}</ref> GroES and GroEL are [[heat shock protein]]s belonging to the family of [[Chaperone (protein)|molecular chaperones]] in bacteria. DNA analyses have shown that the ''GroES'' and ''GroEL'' genes are indeed present in ''O. tsutsugamushi'' with slight variation in different strains, and they produce the 11-kDa and 60-kDa proteins.<ref>{{cite journal |last1=Arai |first1=S. |last2=Tabara |first2=K. |last3=Yamamoto |first3=N. |last4=Fujita |first4=H. |last5=Itagaki |first5=A. |last6=Kon |first6=M. |last7=Satoh |first7=H. |last8=Araki |first8=K. |last9=Tanaka-Taya |first9=K. |last10=Takada |first10=N. |last11=Yoshikawa |first11=Y. |last12=Ishihara |first12=C. |last13=Okabe |first13=N. |last14=Oishi |first14=K. |title=Molecular phylogenetic analysis of ''Orientia tsutsugamushi'' based on the ''groES'' and ''groEL'' genes |journal=Vector Borne and Zoonotic Diseases |date=2013 |volume=13 |issue=11 |pages=825–829 |doi=10.1089/vbz.2012.1155 |pmid=24107204 |pmc=3822374}}</ref>

==Disease==
{{details|Scrub typhus}}
''Orientia tsutsugamushi'' causes a complex and potentially life-threatening disease known as scrub typhus. Infection starts when chiggers bite on the skin during their feeding. The bacteria are deposited at the site of feeding (inoculation), where they multiply. They cause progressive tissue damage ([[necrosis]]), which leads to formation of an [[eschar]] on the skin. 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 including the liver, brain, kidney, [[meninges]] and lungs.<ref name="peter15">{{cite journal|last1=Peter|first1=J.V.|last2=Sudarsan|first2=T.I.|last3=Prakash|first3=J.A.J.|last4=Varghese|first4=G.M.|title=Severe scrub typhus infection: Clinical features, diagnostic challenges and management|journal=World Journal of Critical Care Medicine|date=2015|volume=4|issue=3|pages=244–250|doi=10.5492/wjccm.v4.i3.244|pmid=26261776|pmc=4524821 |doi-access=free }}</ref> The disease is responsible for nearly a quarter of all the febrile (high fever) illness in endemic areas. Mortality in severe cases or due to improper treatment or misdiagnosis may be as high as 30–70%.<ref>{{cite journal |last1=Taylor |first1=A.J. |last2=Paris |first2=D.H. |last3=Newton |first3=P.N. |last4=Walker |first4=D.H. |title=A systematic review of mortality from untreated scrub typhus (''Orientia tsutsugamushi'') |journal=PLOS Neglected Tropical Diseases |date=2015 |volume=9 |issue=8 |pages=e0003971 |doi=10.1371/journal.pntd.0003971 |pmid=26274584 |pmc=4537241 |doi-access=free }}</ref> About 6% of infected people die untreated, and 1.4% of the patients die even with medical treatment. Moreover, the death rate can be as high as 14% with neurological problems and 24% with multi-organ dysfunction among treated patients.<ref name="bonell">{{cite journal |last1=Bonell |first1=A. |last2=Lubell |first2=Y. |last3=Newton |first3=P.N. |last4=Crump |first4=J.A. |last5=Paris |first5=D.H. |title=Estimating the burden of scrub typhus: A systematic review |journal=PLOS Neglected Tropical Diseases |date=2017 |volume=11 |issue=9 |pages=e0005838 |doi=10.1371/journal.pntd.0005838 |pmid=28945755 |pmc=5634655 |doi-access=free }}</ref> 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]], [[subacute thyroiditis]], and [[multiple organ dysfunction syndrome]].<ref name="ReferenceB">{{cite journal|last1=Rajapakse|first1=S.|last2=Weeratunga|first2=P.|last3=Sivayoganathan|first3=S.|last4=Fernando|first4=S.D.|title=Clinical manifestations of scrub typhus|journal=Transactions of the Royal Society of Tropical Medicine and Hygiene|date=2017|volume=111|issue=2|pages=43–54|doi=10.1093/trstmh/trx017|pmid=28449088|s2cid=3751821}}</ref> Harmful effects involving multiple organ failure and neurological impairment are difficult to treat, and can cause lifelong debilitation or be directly fatal.<ref name="ReferenceB"/> The central nervous system is often affected and results in various complications including [[cerebellitis]], [[palsies|cranial nerve palsies]], [[meningoencephalitis]], [[plexopathy]], [[transverse myelitis]], and [[Guillan-Barre Syndrome|Guillan-Barré syndrome]].<ref name=Mahajan>{{cite journal|last1=Mahajan|first1=S.K.|title=Neuropsychiatric manifestations of scrub typhus|journal=Journal of Neurosciences in Rural Practice|date=2017|volume=8|issue=3|pages=421–426|doi=10.4103/jnrp.jnrp_44_17|pmid=28694624|pmc=5488565 |doi-access=free }}</ref> Death rates due to complications can be up to 14% in brain infections, and 24% with multiple organ failure.<ref name="bonell"/> In India, scrub typhus has become the major cause of acute encephalitis syndrome, which was earlier caused mainly by a viral infection, [[Japanese encephalitis]].<ref name=jain18>{{cite journal|last1=Jain|first1=P.|last2=Prakash|first2=S.|last3=Tripathi|first3=P.K.|last4=Chauhan|first4=A.|last5=Gupta|first5=S.|last6=Sharma|first6=U.|last7=Jaiswal|first7=A.K.|last8=Sharma|first8=D.|last9=Jain|first9=A.|title=Emergence of ''Orientia tsutsugamushi'' as an important cause of acute encephalitis syndrome in India|journal=PLOS Neglected Tropical Diseases|date=2018|volume=12|issue=3|pages=e0006346|doi=10.1371/journal.pntd.0006346|pmid=29590177|pmc=5891077 |doi-access=free }}</ref>

===Epidemiology===
[[File:Tsutsugamushi Triangle.tif|thumb|Map showing the Tsutsugamushi Triangle. Countries with human cases are labeled with a star.]]
The [[World Health Organization]] in 1999 stated that:
{{Quote| 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.<ref>{{cite web|last1=WHO|title=WHO Recommended Surveillance Standards (Second edition)|website=WHO/CDS/CSR/ISR/99.2|publisher=World Health Organization, Geneva |url=https://www.who.int/csr/resources/publications/surveillance/WHO_CDS_CSR_ISR_99_2_EN/en/ |archive-url=https://web.archive.org/web/20030418133424/http://www.who.int/csr/resources/publications/surveillance/WHO_CDS_CSR_ISR_99_2_EN/en/ |url-status=dead |archive-date=April 18, 2003 |page=124|date=1999}}</ref>}} 
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 as shown in '''Figure 6'''.<ref name="peter15"/> However, it has spread to Africa, Europe and South America.<ref name="jiang18">{{cite journal|last1=Jiang|first1=J.|last2=Richards|first2=A.L.|title=Scrub typhus: No longer restricted to the Tsutsugamushi Triangle|journal=Tropical Medicine and Infectious Disease|date=2018|volume=3|issue=1|pages=11|doi=10.3390/tropicalmed3010011|pmid=30274409|pmc=6136623|doi-access=free}}</ref> 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.<ref name=xu17/> 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.<ref name=paris13>{{cite journal|last1=Walker|first1=D.H.|last2=Paris|first2=D.H.|last3=Day|first3=N.P.|last4=Shelite|first4=T.R.|title=Unresolved problems related to scrub typhus: A seriously neglected life-threatening disease|journal=The American Journal of Tropical Medicine and Hygiene|date=2013|volume=89|issue=2|pages=301–307|doi=10.4269/ajtmh.13-0064|pmid=23926142|pmc=3741252}}</ref> 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 infections out of 100,000 people in 2013), followed by Japan, Thailand, and China at top of the list. The age group of 60–69 years is at highest risk of infection. Higher infection (57.3%) is seen in females compared to males (42.7%). Farmers are most vulnerable, accounting for 70% of the cases in China. The disease is more prevalent in rural areas, but there is a rapid increase in urban areas. For example, in Korea, the annual incidence increased 21-fold between 2003 and 2013 in metropolitan areas.<ref name="bonell"/>

===Diagnosis===

====Symptom====
The main symptom of ''O. tsutsugamushi'' infection is high (febrile) fever; however, the symptom is similar to other vector-borne tropical diseases such as [[malaria]], [[leptospirosis]], [[typhoid fever|typhoid]], [[murine typhus]], [[chikungunya]], and [[dengue fever]].<ref>{{cite journal |last1=Mørch |first1=K. |last2=Manoharan |first2=A. |last3=Chandy |first3=S. |last4=Chacko |first4=N. |last5=Alvarez-Uria |first5=G. |last6=Patil |first6=S. |last7=Henry |first7=A. |last8=Nesaraj |first8=J. |last9=Kuriakose |first9=C. |last10=Singh |first10=A. |last11=Kurian |first11=S. |last12=Gill Haanshuus |first12=C. |last13=Langeland |first13=N. |last14=Blomberg |first14=B. |last15=Vasanthan Antony |first15=G. |last16=Mathai |first16=D. |title=Acute undifferentiated fever in India: a multicentre study of aetiology and diagnostic accuracy |journal=BMC Infectious Diseases |date=2017 |volume=17 |issue=1 |pages=665 |doi=10.1186/s12879-017-2764-3 |pmid=28978319 |pmc=5628453 |doi-access=free }}</ref><ref>{{cite journal |last1=Wangrangsimakul |first1=T. |last2=Althaus |first2=T. |last3=Mukaka |first3=M. |last4=Kantipong |first4=P. |last5=Wuthiekanun |first5=V. |last6=Chierakul |first6=W. |last7=Blacksell |first7=S.D. |last8=Day |first8=N.P. |last9=Laongnualpanich |first9=A. |last10=Paris |first10=D.H. |title=Causes of acute undifferentiated fever and the utility of biomarkers in Chiangrai, northern Thailand |journal=PLOS Neglected Tropical Diseases |date=2018 |volume=12 |issue=5 |pages=e0006477 |doi=10.1371/journal.pntd.0006477 |pmid=29852003 |pmc=5978881 |doi-access=free }}</ref> 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|the incubation period]]) takes between 6 and 21 days.<ref name="peter15"/> A simple visual diagnosis is the presence of an inflamed scar-like scab 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 ('''Figure 7'''). In rare cases, it can be seen on the cheek, ear lobe and [[Foot|dorsum of the feet]].<ref>{{cite journal |last1=Kundavaram |first1=A.P. |last2=Jonathan |first2=A.J. |last3=Nathaniel |first3=S.D. |last4=Varghese |first4=G.M. |title=Eschar in scrub typhus: a valuable clue to the diagnosis |journal=Journal of Postgraduate Medicine |date=2013 |volume=59 |issue=3 |pages=177–178 |doi=10.4103/0022-3859.118033 |pmid=24029193|doi-access=free }}</ref> 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.<ref>{{cite journal |last1=Varghese |first1=G.M. |last2=Janardhanan |first2=J. |last3=Trowbridge |first3=P. |last4=Peter |first4=J.V. |last5=Prakash |first5=J.A. |last6=Sathyendra |first6=S. |last7=Thomas |first7=K. |last8=David |first8=T.S. |last9=Kavitha |first9=M.L. |last10=Abraham |first10=O.C. |last11=Mathai |first11=D. |title=Scrub typhus in South India: clinical and laboratory manifestations, genetic variability, and outcome |journal=International Journal of Infectious Diseases |date=2013 |volume=17 |issue=11 |pages=e981-987 |doi=10.1016/j.ijid.2013.05.017 |pmid=23891643|doi-access=free }}</ref> Also, eschar is not specific to scrub typhus, occurring in [[Spotted fever|other rickettsial diseases]] such as [[Rocky Mountain spotted fever]],<ref>{{cite journal |last1=Kelman |first1=P. |last2=Thompson |first2=C.W. |last3=Hynes |first3=W. |last4=Bergman |first4=C. |last5=Lenahan |first5=C. |last6=Brenner |first6=J.S. |last7=Brenner |first7=M.G. |last8=Goodman |first8=B. |last9=Borges |first9=D. |last10=Filak |first10=M. |last11=Gaff |first11=H. |title=''Rickettsia parkeri'' infections diagnosed by eschar biopsy, Virginia, USA |journal=Infection |date=2018 |volume=46 |issue=4 |pages=559–563 |doi=10.1007/s15010-018-1120-x |pmid=29383651|s2cid=30442009 }}</ref> Brazilian spotted fever,<ref>{{cite journal |last1=Silva |first1=N. |last2=Eremeeva |first2=M.E. |last3=Rozental |first3=T. |last4=Ribeiro |first4=G.S. |last5=Paddock |first5=C.D. |last6=Ramos |first6=E.A. |last7=Favacho |first7=A.R. |last8=Reis |first8=M.G. |last9=Dasch |first9=G.A. |last10=de Lemos |first10=E.R. |last11=Ko |first11=A.I. |title=Eschar-associated spotted fever rickettsiosis, Bahia, Brazil |journal=Emerging Infectious Diseases |date=2011 |volume=17 |issue=2 |pages=275–278 |doi=10.3201/eid1702.100859 |pmid=21291605 |pmc=3204763}}</ref> and Indian tick typhus.<ref>{{cite journal |last1=Hulmani |first1=M. |last2=Alekya |first2=P. |last3=Kumar |first3=V.J. |title=Indian tick typhus presenting as purpura fulminans with review on rickettsial infections |journal=Indian Journal of Dermatology |date=2017 |volume=62 |issue=1 |pages=1–6 |doi=10.4103/0019-5154.198030 |pmid=28216718 |pmc=5286740 |doi-access=free }}</ref><ref>{{cite journal|last1=Walker|first1=D.H.|title=Rickettsioses of the spotted fever group around the world|journal=The Journal of Dermatology|date=1989|volume=16|issue=3|pages=169–177|pmid=2677080|doi=10.1111/j.1346-8138.1989.tb01244.x|s2cid=21977403}}</ref> Using DNA analysis by advanced polymerase chain reaction, different rickettsial infections can be identified from eschars.<ref>{{cite journal |last1=Denison |first1=A.M. |last2=Amin |first2=B.D. |last3=Nicholson |first3=W.L. |last4=Paddock |first4=C.D. |title=Detection of ''Rickettsia rickettsii'', ''Rickettsia parkeri'', and ''Rickettsia akari'' in skin biopsy specimens using a multiplex real-time polymerase chain reaction assay |journal=Clinical Infectious Diseases |date=2014 |volume=59 |issue=5 |pages=635–642 |doi=10.1093/cid/ciu358 |pmid=24829214 |pmc=4568984}}</ref>

====Blood test====
Suspected infections are confirmed with serological tests. ''O. tsutsugamushi'' is most often detected from blood serum using the [[Weil–Felix test]]. Weil–Felix is the simplest and most rapid test, but it is not sensitive or specific, as it detects any kind of rickettsial infection. More sensitive tests such as rapid immunochromatographic test (RICT), immunofluorescence assays (IFA), ELISA, and DNA analysis using polymerase chain reaction (PCR) are used.<ref name="luce18"/><ref name=koh/> IFA is regarded as the gold standard test, as it gives a reliable result; however, it is expensive and not specific for different rickettsial bacteria.<ref>{{cite journal |last1=Koraluru |first1=M. |last2=Bairy |first2=I. |last3=Varma |first3=M. |last4=Vidyasagar |first4=S. |title=Diagnostic validation of selected serological tests for detecting scrub typhus |journal=Microbiology and Immunology |date=2015 |volume=59 |issue=7 |pages=371–374 |doi=10.1111/1348-0421.12268 |pmid=26011315|s2cid=49921 |doi-access=free }}</ref> ELISA and PCR can detect ''O. tsutsugamushi''-specific proteins such as the TSA56 and GroEL, so that they are highly specific and sensitive.<ref>{{cite journal |last1=Patricia |first1=K.A. |last2=Hoti |first2=S.L. |last3=Kanungo |first3=R. |last4=Jambulingam |first4=P. |last5=Shashikala |first5=N. |last6=Naik |first6=A.C. |title=Improving the diagnosis of scrub typhus by combining ''groEL''-based polymerase chain reaction and IgM ELISA |journal=Journal of Clinical and Diagnostic Research |date=2017 |volume=11 |issue=8 |pages=DC27–DC31 |doi=10.7860/JCDR/2017/26523.10519 |pmid=28969124 |pmc=5620764}}</ref> On the other hand, they are highly sophisticated and expensive techniques.

===Treatment===
''Orientia 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 its high efficacy and quick action. But, in pregnant women and babies, it is [[contraindication|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.<ref>{{cite journal |last1=Rahi |first1=M. |last2=Gupte |first2=M.D. |last3=Bhargava |first3=A. |last4=Varghese |first4=G.Mm |last5=Arora |first5=R. |title=DHR-ICMR Guidelines for diagnosis & management of rickettsial diseases in India |journal=Indian Journal of Medical Research |date=2015 |volume=141 |issue=4 |pages=417–22 |doi=10.4103/0971-5916.159279 |pmid=26112842 |pmc=4510721 |doi-access=free }}</ref> A randomized controlled trial and systematic review showed that azithromycin is the safest medication.<ref>{{cite journal |last1=Chanta |first1=C. |last2=Phloenchaiwanit |first2=P. |title=Randomized Controlled trial of azithromycin versus doxycycline or chloramphenicol for treatment of uncomplicated pediatric scrub typhus |journal=Journal of the Medical Association of Thailand |date=2015 |volume=98 |issue=8 |pages=756–760 |pmid=26437532}}</ref><ref>{{cite journal |last1=Lee |first1=S.C. |last2=Cheng |first2=Y.J. |last3=Lin |first3=C.H. |last4=Lei |first4=W.T. |last5=Chang |first5=H.Y. |last6=Lee |first6=M.D. |last7=Liu |first7=J.M. |last8=Hsu |first8=R.J. |last9=Chiu |first9=N.C. |last10=Chi |first10=H. |last11=Peng |first11=C.C. |last12=Tsai |first12=T.L. |last13=Lin |first13=C.Y. |title=Comparative effectiveness of azithromycin for treating scrub typhus |journal=Medicine |date=2017 |volume=96 |issue=36 |pages=e7992 |doi=10.1097/MD.0000000000007992 |pmid=28885357 |pmc=6392745}}</ref>

===Vaccine===
No licensed ''O. tsutsugamushi'' vaccines are currently available. The first vaccines were developed in the late 1940s, but failed in clinical trials.<ref>{{cite journal |last1=Card |first1=W.I. |last2=Walker |first2=J.M. |title=Scrub-typhus vaccine; field trial in South-east Asia |journal=Lancet |date=1947 |volume=1 |issue=6450 |pages=481–483 |pmid=20294827 |doi=10.1016/S0140-6736(47)91989-2}}</ref><ref>{{cite journal |last1=Berge |first1=T.O. |last2=Gauld |first2=R.L. |last3=Kitaoka |first3=M. |title=A field trial of a vaccine prepared from the Volner strain of ''Rickettsia tsutsugamushi'' |journal=American Journal of Hygiene |date=1949 |volume=50 |issue=3 |pages=337–342 |pmid=15391985|doi=10.1093/oxfordjournals.aje.a119366}}</ref> Considered an ideal target, the unique TSA56 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.<ref name=valbuena>{{cite journal |last1=Valbuena |first1=G. |last2=Walker |first2=D. H. |title=Approaches to vaccines against ''Orientia tsutsugamushi'' |journal=Frontiers in Cellular and Infection Microbiology |date=2013 |volume=2 |page=127 |doi=10.3389/fcimb.2012.00170 |pmid=23316486 |pmc=3539663|doi-access=free }}</ref> A vaccine targeting the 47-kDa outer membrane protein (OMP) is a promising candidate with experimental success in mice against the Boryong strain.<ref>{{cite journal |last1=Choi |first1=S. |last2=Jeong |first2=H.J. |last3=Hwang |first3=K.J. |last4=Gill |first4=B. |last5=Ju |first5=Y.R. |last6=Lee |first6=Y.S. |last7=Lee |first7=J. |title=A recombinant 47-kDa outer membrane protein induces an immune response against ''Orientia tsutsugamushi'' strain Boryong |journal=The American Journal of Tropical Medicine and Hygiene |date=2017 |volume=97 |issue=1 |pages=30–37 |doi=10.4269/ajtmh.15-0771 |pmid=28719308 |pmc=5508880}}</ref> Combined targeting of TSA56 and ScaA is also a good candidate for mixed-strain infection.<ref name=ha15/>

==Immunity==
There is no lasting immunity to ''O. tsutsugamushi'' infection. Antigenic variation prevents the development of cross immunity to the various strains of ''O. tsutsugamushi''. 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.<ref name=valbuena/> An immunisation experiment was done in 1950 in which 16 volunteers still developed the infection after 11–25 months of primary infection.<ref>{{cite journal |last1=Smadel |first1=JE |last2=Ley |first2=H.L.Jr. |last3=Diercks |first3=F.H. |last4=Traub |first4=R. |title=Immunity in scrub typhus: resistance to induced reinfection |journal=A.M.A. Archives of Pathology |date=1950 |volume=50 |issue=6 |pages=847–861 |pmid=14789327}}</ref> 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 in monkeys.<ref>{{cite journal |last1=MacMillan |first1=J.G. |last2=Rice |first2=R.M. |last3=Jerrells |first3=T.R. |title=Development of antigen-specific cell-mediated immune responses after infection of cynomolgus monkeys (''Macaca fascicularis'') with ''Rickettsia tsutsugamushi'' |journal=The Journal of Infectious Diseases |date=1985 |volume=152 |issue=4 |pages=739–749 |pmid=2413138|doi=10.1093/infdis/152.4.739}}</ref> But in humans, immunity declines after one year, and disappears within two years.<ref>{{cite journal |last1=Ha |first1=N.Y. |last2=Kim |first2=Y. |last3=Min |first3=C.K. |last4=Kim |first4=H.I. |last5=Yen |first5=N.T.H. |last6=Choi |first6=M.S. |last7=Kang |first7=J.S. |last8=Kim |first8=Y.S. |last9=Cho |first9=N.H. |title=Longevity of antibody and T-cell responses against outer membrane antigens of ''Orientia tsutsugamushi'' in scrub typhus patients |journal=Emerging Microbes & Infections |date=2017 |volume=6 |issue=12 |pages=e116 |doi=10.1038/emi.2017.106 |pmid=29259327 |pmc=5750460}}</ref>

==References==
{{Academic peer reviewed|Q73054107|doi-access=free}}
{{Reflist|30em}}

{{Gram-negative bacterial diseases}}
{{Taxonbar|from=Q3018329}}

[[Category:Rickettsiaceae]]
[[Category:Bacteria described in 1995]]
[[Category:Rickettsioses]]

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Module:Cite Q (view source) (template editor protected)
Module:Complex date (view source) (template editor protected)
Module:DateI18n (view source) (template editor protected)
Module:Delink (view source) (protected)
Module:Disambiguation/templates (view source) (protected)
Module:Format link (view source) (template editor protected)
Module:GetParameters (view source) (template editor protected)
Module:Hatnote (view source) (template editor protected)
Module:Hatnote/styles.css (view source) (template editor protected)
Module:Hatnote list (view source) (template editor protected)
Module:I18n/complex date (view source) (template editor protected)
Module:ISOdate (view source) (template editor protected)
Module:If empty (view source) (protected)
Module:InfoboxImage (view source) (template editor protected)
Module:Italic title (view source) (template editor protected)
Module:Labelled list hatnote (view source) (template editor protected)
Module:Namespace detect/config (view source) (protected)
Module:Namespace detect/data (view source) (protected)
Module:Navbar (view source) (protected)
Module:Navbar/configuration (view source) (protected)
Module:Navbar/styles.css (view source) (protected)
Module:Navbox (view source) (template editor protected)
Module:Navbox/configuration (view source) (template editor protected)
Module:Navbox/styles.css (view source) (template editor protected)
Module:Pagetype (view source) (protected)
Module:Pagetype/config (view source) (protected)
Module:Pagetype/disambiguation (view source) (protected)
Module:Pagetype/rfd (view source) (protected)
Module:Pagetype/setindex (view source) (protected)
Module:Pagetype/softredirect (view source) (protected)
Module:ResolveEntityId (view source) (template editor protected)
Module:SDcat (view source) (protected)
Module:String (view source) (protected)
Module:String2 (view source) (template editor protected)
Module:TableTools (view source) (protected)
Module:TaxonItalics (view source) (template editor protected)
Module:Taxonbar (view source) (template editor protected)
Module:Taxonbar/candidate (view source) (template editor protected)
Module:Taxonbar/conf (view source) (template editor protected)
Module:Taxonbar/exists (view source) (template editor protected)
Module:Taxonbar/whitelist (view source) (template editor protected)
Module:Template redirect regex (view source) (template editor protected)
Module:Wd (view source) (template editor protected)
Module:Wd/i18n (view source) (template editor protected)
Module:WikidataIB (view source) (template editor protected)
Module:WikidataIB/nolinks (view source) (template editor protected)
Module:WikidataIB/titleformats (view source) (template editor protected)
Module:Wikitext Parsing (view source) (protected)
Module:Yesno (view source) (protected)

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