Editing Leishmania

{{Short description|Genus of parasitic flagellate protist}}
{{About|the parasite|the infection|Leishmaniasis}}
{{italic title}}
{{Automatic taxobox
| taxon = Leishmania
| image = Leishmania_donovani_01.png
| image_caption = ''L. donovani'' in bone marrow cell
| authority = [[Ronald Ross|Ross]], 1903
| subdivision_ranks = Species
| subdivision = ''[[Leishmania aethiopica|L. aethiopica]]''<br />
''[[Leishmania amazonensis|L. amazonensis]]''<br />
''[[Leishmania arabica|L. arabica]]''<br />
''[[Leishmania archibaldi|L. archibaldi]]'' (starus species)<br />
''[[Leishmania aristedesi|L. aristedesi]]'' (status disputed)<br />
''[[Leishmania braziliensis|L. (Viannia) braziliensis]]''<br />
''[[Leishmania chagasi|L. chagasi]]'' (syn. ''L. infantum'')<br />
''[[Leishmania donovani|L. donovani]]''<br />
''[[Leishmania enriettii|L. (Mundinia) enriettii]]''<br />
''[[Leishmania forattinii|L. forattinii]]'' (status disputed)<br />
''[[Leishmania garnhami|L. garnhami]]'' (status disputed)<br />
''[[Leishmania gerbili|L. gerbili]]''<br />
''[[Leishmania guyanensis|L. (Viannia) guyanensis]]''<br />
''[[Leishmania infantum|L. infantum]]''<br />
''[[Leishmania killicki|L. killicki]]'' (status disputed)<br />
''[[Leishmania lainsoni|L. (Viannia) lainsoni]]''<br />
''[[Leishmania major|L. major]]''<br />
''[[Leishmania macropodum|L. (Mundinia) macropodum]]''<br />
''[[Leishmania martiniquensis|L. (Mundinia) martiniquensis]]''<br />
''[[Leishmania mexicana|L. mexicana]]''<br />
''[[Leishmania naiffi|L. (Viannia) naiffi]]''<br />
''[[Leishmania panamensis|L. (Viannia) panamensis]]''<br />
''[[Leishmania peruviana|L. (Viannia) peruviana]]''<br />
''[[Leishmania pifanoi|L. pifanoi]]'' (status disputed)<br />
''[[Leishmania shawi|L. (Viannia) shawi]]''<br />
''[[Leishmania tarentolae|L. tarentolae]]''<br />
''[[Leishmania tropica|L. tropica]]''<br />
''[[Leishmania turanica|L. turanica]]''<br />
''[[Leishmania waltoni|L. waltoni]]''<br />
''[[Leishmania venezuelensis|L. venezuelensis]]''
}}

'''''Leishmania''''' ({{IPAc-en|l|iː|ʃ|ˈ|m|eɪ|n|i|ə|,_|-|ˈ|m|æ|n|-}}<ref>{{Cite book|title=The Chambers Dictionary|publisher=Chambers|year=2003|isbn=0-550-10105-5|edition=9th|chapter=leishmania}}</ref>) is a genus of parasitic [[Protozoa|protozoans]], single-celled [[Eukaryote|eukaryotic]] organisms of the [[trypanosomatid]] group that are responsible for the disease [[leishmaniasis]].<ref name="Sherris">{{cite book |author= |title=Sherris Medical Microbiology |publisher=McGraw Hill |year=2004 |isbn=0-8385-8529-9 |editor-last=Ryan |editor-first=KJ |edition=4th |pages=749–54 |editor-last2=Ray |editor-first2=CG}}</ref><ref name="MylerP">{{cite book |author= |title=Leishmania: After The Genome |publisher=Caister Academic Press |year=2008 |isbn=978-1-904455-28-8 |editor-last=Myler |editor-first=P |editor-last2=Fasel |editor-first2=N}}</ref><ref name="pmid26616453">{{cite journal |last1=Ansari |first1=Md Yousuf |last2=Equbal |first2=Asif |last3=Dikhit |first3=Manas Ranjan |last4=Mansuri |first4=Rani |last5=Rana |first5=Sindhuprava |last6=Ali |first6=Vahab |last7=Sahoo |first7=Ganesh Chandra |last8=Das |first8=Pradeep |title=Establishment of correlation between in-silico and in-vitro test analysis against Leishmania HGPRT to inhibitors |journal=International Journal of Biological Macromolecules |date=February 2016 |volume=83 |pages=78–96 |doi=10.1016/j.ijbiomac.2015.11.051}}</ref> The parasites are transmitted by [[Phlebotominae|sandflies]] of the genus ''[[Phlebotomus]]'' in the [[Old World]], and of the genus ''[[Lutzomyia]]'' in the [[New World]]. There are 53 species and about 20 of them are responsible for human infections.<ref>{{Cite journal |last=Georgiadou |first=Sarah P. |last2=Makaritsis |first2=Konstantinos P. |last3=Dalekos |first3=George N. |date=2015 |title=Leishmaniasis revisited: Current aspects on epidemiology, diagnosis and treatment |url=https://www.degruyterbrill.com/document/doi/10.1515/jtim-2015-0002/html |journal=Journal of Translational Internal Medicine |volume=3 |issue=2 |pages=43–50 |doi=10.1515/jtim-2015-0002 |pmc=4936444 |pmid=27847886}}</ref><ref name=":1">{{Cite journal |last=Herrera |first=Giovanny |last2=Barragán |first2=Natalia |last3=Luna |first3=Nicolás |last4=Martínez |first4=David |last5=De Martino |first5=Frasella |last6=Medina |first6=Julián |last7=Niño |first7=Sergio |last8=Páez |first8=Luisa |last9=Ramírez |first9=Angie |last10=Vega |first10=Laura |last11=Velandia |first11=Valeria |last12=Vera |first12=Michelle |last13=Zúñiga |first13=María Fernanda |last14=Bottin |first14=Marius Jean |last15=Ramírez |first15=Juan David |display-authors=8 |date=2020-04-03 |title=An interactive database of Leishmania species distribution in the Americas |url=https://www.nature.com/articles/s41597-020-0451-5 |journal=Scientific Data |volume=7 |issue=1 |pages=110 |doi=10.1038/s41597-020-0451-5 |issn=2052-4463 |pmc=7125201 |pmid=32245983}}</ref> They are transmitted by around 100 species of sandflies.<ref name=":2">{{Cite journal |last=Cecílio |first=Pedro |last2=Cordeiro-da-Silva |first2=Anabela |last3=Oliveira |first3=Fabiano |date=2022-04-04 |title=Sand flies: Basic information on the vectors of leishmaniasis and their interactions with Leishmania parasites |url=https://www.nature.com/articles/s42003-022-03240-z |journal=Communications Biology |volume=5 |issue=1 |pages=305 |doi=10.1038/s42003-022-03240-z |issn=2399-3642 |pmc=8979968 |pmid=35379881}}</ref> The primary hosts are [[vertebrate]]s. They commonly infect [[hyrax]]es, [[canid]]s, [[rodent]]s, and [[human]]s.

==History==
Members of an ancient [[genus]] of  ''Leishmania''-like parasites, ''[[Paleoleishmania]]'', have been detected in [[fossilized]] [[sand flies]] dating back to the early [[Cretaceous]] period.<ref>{{cite journal |last1=Poinar |first1=G |year=2008 |title=Lutzomyia adiketis sp. n. (Diptera: Phlebotomidae), a vector of Paleoleishmania neotropicum sp. n. (Kinetoplastida: Trypanosomatidae) in Dominican amber |journal=Parasit Vectors |volume=1 |issue=1 |page=2 |doi=10.1186/1756-3305-1-22 |pmc=2491605 |pmid=18627624 |doi-access=free }}</ref> The first written reference to the conspicuous symptoms of [[cutaneous leishmaniasis]] surfaced in the [[Paleotropics]] within [[oriental]] texts dating back to the 7th century BC (allegedly transcribed from sources several hundred years older, between 1500 and 2000 BC<ref>{{cite journal |doi=10.1128/CMR.15.4.595-612.2002 |pmid=12364371 |pmc=126866 |title=History of Human Parasitology |journal=Clinical Microbiology Reviews |volume=15 |issue=4 |pages=595–612 |year=2002 |last1=Cox |first1=F. E. G }}</ref>). Due to its broad and persistent prevalence throughout antiquity as a mysterious disease of diverse symptomatic outcomes, leishmaniasis has been dubbed with various names ranging from "white leprosy" to "[[black fever]]". Some of these names suggest links to negative cultural beliefs or mythology, which still feed into the social stigmatization of leishmaniasis today.<ref>{{cite journal |last1=Yanik |first1=M. |last2=Gurel |first2=M. S. |last3=Simsek |first3=Z. |last4=Kati |first4=M. |title=The psychological impact of cutaneous leishmaniasis |journal=Clinical and Experimental Dermatology |date=September 2004 |volume=29 |issue=5 |pages=464–467 |doi=10.1111/j.1365-2230.2004.01605.x |pmid = 15347324|s2cid = 11543741}}</ref>

In India, both cutaneous and [[visceral leishmaniasis]] are caused by ''[[Leishmania donovani]]''.<ref>{{Cite journal |last1=Thakur |first1=Lovlesh |last2=Singh |first2=Kiran K. |last3=Shanker |first3=Vinay |last4=Negi |first4=Ajeet |last5=Jain |first5=Aklank |last6=Matlashewski |first6=Greg |last7=Jain |first7=Manju |date=2018 |title=Atypical leishmaniasis: A global perspective with emphasis on the Indian subcontinent |journal=PLOS Neglected Tropical Diseases |volume=12 |issue=9 |pages=e0006659 |doi=10.1371/journal.pntd.0006659 |issn=1935-2735 |pmc=6159859 |pmid=30260957 |doi-access=free }}</ref><ref>{{Cite journal |last1=Thakur |first1=Lovlesh |last2=Singh |first2=Kiran K. |last3=Kushwaha |first3=Hemant R. |last4=Sharma |first4=Sudarshan K. |last5=Shankar |first5=Vinay |last6=Negi |first6=Ajeet |last7=Verma |first7=Ghanshyam |last8=Kumari |first8=Sandhya |last9=Jain |first9=Aklank |last10=Jain |first10=Manju |date=2020 |title=Leishmania donovani Infection with Atypical Cutaneous Manifestations, Himachal Pradesh, India, 2014-2018 |journal=Emerging Infectious Diseases |volume=26 |issue=8 |pages=1864–1869 |doi=10.3201/eid2608.191761 |issn=1080-6059 |pmc=7392404 |pmid=32687048}}</ref> The first records of cutaneous leishmaniasis in India were from British medical officers in the early 19th century. The disease was by then known as "oriental sore" or "Delhi boil";<ref>{{Cite journal |last=Steverding |first=Dietmar |date=2017 |title=The history of leishmaniasis |journal=Parasites & Vectors |volume=10 |issue=1 |pages=82 |doi=10.1186/s13071-017-2028-5 |issn=1756-3305 |pmc=5312593 |pmid=28202044 |doi-access=free }}</ref> while the visceral form was variously called "Burdwan [after the city [[Burdwan]]] fever", "''kala azar"'' (black fever), or "Dumdum [<nowiki/>[[Dum Dum|a city]] in West Bengal] fever".<ref>{{Cite journal |last=Cox |first=Francis E. G. |date=2017 |title=The Golden Age of parasitology-1875-1925: the Scottish contributions |url=https://pubmed.ncbi.nlm.nih.gov/27628769 |journal=Parasitology |volume=144 |issue=12 |pages=1567–1581 |doi=10.1017/S0031182016001566 |issn=1469-8161 |pmid=27628769|s2cid=30381476 }}</ref>

The causative parasite for the disease was identified in 1901 as a concurrent finding by [[William Boog Leishman]] and [[Charles Donovan]]. They independently visualised microscopic single-celled parasites (later called Leishman-Donovan bodies) living within the cells of infected human organs. The parasitic genus would later be classed as [[trypanosomatid]] [[protozoans]] under the [[phylogenetic]] designation, ''Leishmania donovani''. Several species have since been classified and grouped under two major subgenera i.e. ''Leishmania Viannia'' (generally located in the [[Neotropics]])  or ''Leishmania Leishmania'' (generally located in the [[Paleotropics]], with the major exception of the ''[[Leishmania mexicana|L. mexicana]]'' subgroup).<ref name=":0" />

==Epidemiology==
''Leishmania'' currently affects 6 million people in 98 countries. About 0.9–1.6 million new cases occur each year, and 21 species are known to cause disease in humans: it is considered a [[zoonosis]].

==Structure==
''Leishmania'' species are [[protist|unicellular eukaryote]]s having a well-defined [[Cell nucleus|nucleus]] and other cell organelles including [[kinetoplast]]s and [[flagella]]. Depending on the stage of their life cycle, they exist in two structural variants, as:<ref name=dna>{{cite web|title=Morphology and Life Cycle|url=http://dna.kdna.ucla.edu/parasite_course-old/leish_files/subchapters/morphology%20and%20life%20cycle.htm|publisher=UCLA|access-date=24 January 2014}}</ref><ref>{{cite journal|last=Pulvertaft|first=RJ|author2=Hoyle, GF |title=Stages in the life-cycle of Leishmania donovani.|journal=Transactions of the Royal Society of Tropical Medicine and Hygiene|year=1960|volume=54|issue=2|pages=191–6|doi=10.1016/0035-9203(60)90057-2|pmid=14435316}}</ref>  
#The '''amastigote''' form is found in the mononuclear phagocytes and circulatory systems of humans. It is an intracellular and nonmotile form, being devoid of external flagella. The short flagellum is embedded at the anterior end without projecting out. It is oval in shape, and measures 3–6&nbsp;μm in length and 1–3&nbsp;μm in breadth. The kinetoplast and basal body lie towards the anterior end.
#The '''promastigote''' form is found in the [[alimentary tract]] of sandflies. It is an extracellular and motile form. It is considerably larger and highly elongated, measuring 15-30&nbsp;μm in length and 5&nbsp;μm in width. It is spindle-shaped, tapering at both ends. A long flagellum (about the body length) is projected externally at the anterior end. The nucleus lies at the centre, and in front of it are the kinetoplast and the basal body.
[[File:Leish amastig macrofago.jpg|thumb|''L. infantum'' amastigote forms]]

==Evolution==
The details of the evolution of this genus are debated, but ''Leishmania'' apparently evolved from an ancestral trypanosome lineage. The oldest lineage is that of the [[Bodonidae]], followed by ''[[Trypanosoma brucei]]'', the latter being confined to the African continent. ''[[Trypanosoma cruzi]]'' groups with [[Trypanosoma|trypanosome]]s from bats, South American mammals, and [[kangaroo]]s suggest an origin in the Southern Hemisphere. These clades are only distantly related.

The remaining clades in this tree are ''[[Blastocrithidia]]'', ''[[Herpetomonas]]'', and ''[[Phytomonas]]''. The four genera ''[[Leptomonas]]'', ''[[Crithidia]]'', ''Leishmania'', and ''[[Endotrypanum]]'' form the terminal branches, suggesting a relatively recent origin. Several of these genera may be polyphyletic and may need further division.<ref name=Hughes2003>{{cite journal|last1 = Hughes|first1 = AL|last2 = Piontkivska|first2 = H |title = Phylogeny of Trypanosomatidae and Bodonidae (Kinetoplastida) based on 18S rRNA: evidence for paraphyly of ''Trypanosoma'' and six other genera|journal = Mol Biol Evol|volume = 20|issue = 4|pages = 644–652|doi=10.1093/molbev/msg062|pmid = 12679543|year = 2003|doi-access = free}}</ref>

The origins of genus ''Leishmania'' itself are unclear.<ref name=Momen_2000>{{cite journal |last1=Momen |first1=Hooman |last2=Cupolillo |first2=Elisa |title=Speculations on the origin and evolution of the genus Leishmania |journal=Memórias do Instituto Oswaldo Cruz |date=August 2000 |volume=95 |issue=4 |pages=583–588 |doi=10.1590/S0074-02762000000400023 | pmid = 10904419 | doi-access = free }}</ref><ref name=Noyes_2000>{{cite journal |last1=Noyes |first1=Ha |last2=Morrison |first2=Da |last3=Chance |first3=Ml |last4=Ellis |first4=Jt |title=Evidence for a neotropical origin of Leishmania |journal=Memórias do Instituto Oswaldo Cruz |date=August 2000 |volume=95 |issue=4 |pages=575–578 |doi=10.1590/S0074-02762000000400021|pmid = 10904417|doi-access = free}}</ref> One theory proposes an African origin, with migration to the Americas. Another proposes migration from the Americas to the [[Old World]] via the [[Bering Strait]] land bridge around 15 million years ago. A third theory proposes a [[Palearctic realm|Palearctic]] origin.<ref name=Kerr_2000>{{cite journal | author = Kerr SF | title = Palaearctic origin of Leishmania | journal = Mem. Inst. Oswaldo Cruz | volume = 95 | issue = 1 | pages = 75–80 | year = 2000 | pmid = 10656708 | doi = 10.1590/S0074-02762000000100011| doi-access = free }}</ref> Such migrations would entail subsequent migration of vector and reservoir or successive adaptations along the way. A more recent migration is that of ''L. infantum'' from Mediterranean countries to [[Latin America]] (known as ''L. chagasi''), since European colonization of the [[New World]], where the parasites picked up their current New World [[Vector (epidemiology)|vectors]] in their respective ecosystems.<ref>{{cite journal|last=Kuhls|first=Katrin|author2=Alam, Mohammad Zahangir |author3=Cupolillo, Elisa |author4=Ferreira, Gabriel Eduardo M. |author5=Mauricio, Isabel L. |author6=Oddone, Rolando |author7=Feliciangeli, M. Dora |author8=Wirth, Thierry |author9=Miles, Michael A. |author10=Schönian, Gabriele |author11=Kamhawi, Shaden|title=Comparative Microsatellite Typing of New World Leishmania infantum Reveals Low Heterogeneity among Populations and Its Recent Old World Origin|journal=PLOS Neglected Tropical Diseases|date=7 June 2011|volume=5|issue=6|pages=e1155|doi=10.1371/journal.pntd.0001155|pmid=21666787|pmc=3110170 |doi-access=free }}</ref>  This is the cause of the epidemics now evident. One recent New World epidemic concerns foxhounds in the USA.<ref>{{Cite journal | last1 = Duprey | first1 = Z. H. | last2 = Steurer | first2 = F. J. | last3 = Rooney | first3 = J. A. | last4 = Kirchhoff | first4 = L. V. | last5 = Jackson | first5 = J. E. | last6 = Rowton | first6 = E. D. | last7 = Schantz | first7 = P. M. | doi = 10.3201/eid1203.050811 | title = Canine Visceral Leishmaniasis, United States and Canada, 2000–2003 | journal = Emerging Infectious Diseases | volume = 12 | issue = 3 | pages = 440–446 | year = 2006 | pmid =  16704782| pmc =3291440 }}</ref>

Although it was suggested that ''Leishmania'' might have evolved in the [[Neotropics]],<ref name=Noyes1997>{{cite journal|last1 = Noyes|first1 = HA|last2 = Arana|first2 = BA| last3 = Chance|first3 = ML|last4 = Maingon|first4 = R|year = 1997|title = The ''Leishmania hertigi'' (Kinetoplastida; Trypanosomatidae) complex and the lizard ''Leishmania'': their classification and evidence for a neotropical origin of the ''Leishmania''-''Endotrypanum'' clade |journal = J Eukaryot Microbiol|volume = 44|issue = 5|pages = 511–557|doi=10.1111/j.1550-7408.1997.tb05732.x|pmid = 9304821|s2cid = 27460253}}</ref> this is probably true for species belonging to the subgenera ''Viannia'' and ''Endotrypanum''. However, there is evidence that the primary evolution of the subgenera ''Leishmania'' and ''Sauroleishmania'' is the Old World. While the ''Mundinia'' species appear to be more universal in their evolution. One theory is that different lineages became isolated geographically during different periods and it is this that gave rise to this evolutionary mosaicism. But there is no doubt that the Leishmaniinae are a monophyletic group.

A large data set analysis suggests that ''Leishmania'' evolved 90 to 100 million years ago in [[Gondwana]].<ref name=Harkins2015>{{cite journal |doi=10.1016/j.meegid.2015.11.030 |pmid=26708057 |title=Phylogenomic reconstruction supports supercontinent origins for Leishmania |journal=Infection, Genetics and Evolution |volume=38 |pages=101–9 |year=2016 |last1=Harkins |first1=Kelly M |last2=Schwartz |first2=Rachel S |last3=Cartwright |first3=Reed A |last4=Stone |first4=Anne C |doi-access=free }}</ref> The reptile infecting species originated in mammalian clades.

''Sauroleishmania'' species were originally defined on the basis that they infected [[reptile]]s ([[lizard]]s) rather than [[mammal]]s. Based on molecular evidences, they have been moved to subgenus status within ''Leishmania''. This subgenus probably evolved from a group that originally infected mammals.<ref name=Croan1997>{{cite journal |doi=10.1016/S0166-6851(97)00111-4 |pmid=9364962 |title=Evolution of the genus Leishmania revealed by comparison of DNA and RNA polymerase gene sequences |journal=Molecular and Biochemical Parasitology |volume=89 |issue=2 |pages=149–59 |year=1997 |last1=Croan |first1=David G |last2=Morrison |first2=David A |last3=Ellis |first3=John T }}</ref>

==Taxonomy==

53 species are recognised in this genus. The status of several of these is disputed, so the final number may differ.<ref name=":1" /> At least 20 species infect humans.<ref name=":2" /> To make things more complex, [[Hybrid (biology)|hybrids]] might be involved, as it has been reported in Brazil with a hybrid between ''Leishmania (V.) guyanensis'' and ''Leishmania (V.) shawi shawi''.<ref>{{cite journal | last1 = Jennings | first1 = Y. L. | last2 = de Souza | first2 = A. A. A. | last3 = Ishikawa | first3 = E. A. | last4 = Shaw | first4 = J. | last5 = Lainson | first5 = R. | last6 = Silveira | first6 = F. | year = 2014 | title = Phenotypic characterization of ''Leishmania'' spp. causing cutaneous leishmaniasis in the lower Amazon region, western Pará state, Brazil, reveals a putative hybrid parasite, ''Leishmania (Viannia) guyanensis'' × ''Leishmania (Viannia) shawi shawi'' | journal = Parasite | volume = 21 | page = 39 | doi = 10.1051/parasite/2014039 | pmid = 25083790 | pmc = 4118625 }}</ref>

The genus is presently divided into 4 subgenera: ''Leishmania'', ''Sauroleishmania'', ''Mundinia'' and ''Viannia''. The division into the two subgenera (''Leishmania'' and ''Viannia'') was made by Lainson and Shaw in 1987 on the basis of their location within the insect gut. The species in the ''Viannia'' subgenus develop in the hind gut:  ''L. (V.) braziliensis'' has been proposed as the type species for this subgenus. This division has been confirmed by all subsequent studies. Shaw, Camargo and Teixeira created the subgenus ''Mundinia'' while revising Leishmaniinae in 2016.<ref name="pmid27976601">{{cite journal | last1 = Espinosa | first1 = O.A. | last2 = Serrano | first2 = M.G. | last3 = Camargo | first3 = E.P. | first4 = Teixeira | last4 = M.M.G. | first5 = Shaw | last5 =  J.J. | year = 2016 | title = An appraisal of the taxonomy and nomenclature of trypanosomatids presently classified as ''Leishmania' 'and' 'Endotrypanum'' | journal = Parasitology | volume= 145| issue = 4 | pages= 430–442| doi=10.1017/S0031182016002092 | pmid = 27976601| s2cid = 41544524 }}</ref>

''[[Endotrypanum schaudinni|Endotrypanum]]'' is closely related to ''Leishmania''. Some ''Endotypanum'' species are unique in that they infect the erythrocytes of their hosts (sloths). All species are confined to Central and South America.<ref>{{cite journal | last1 = Franco | first1 = AM | last2 = Grimaldi | first2 = G Jr | year = 1999 | title = Characterization of ''Endotrypanum'' (Kinetoplastida: Trypanosomatidae), a unique parasite infecting the neotropical tree sloths (Edentata) | journal = Mem Inst Oswaldo Cruz | volume = 94 | issue = 2| pages = 261–268 | doi=10.1590/s0074-02761999000200026| pmid = 10224540 | doi-access = free }}</ref> ''E. colombiensis'' infections have been found in man.

''Sauroleishmania'' was originally described by Ranquein 1973 as a separate genus, but molecular studies suggest this is actually a subgenus rather than a separate genus.

The proposed division of the ''Leishmania'' into ''[[Euleishmania]]'' and ''[[Paraleishmania]]'' groups in 2000 emphasized the deep phylogenic distance between parasites, some of which had been named as ''Leishmania'' species.<ref name=Momen2000>{{cite journal | last1 = Momen | first1 = H | last2 = Cupolillo | first2 = E | year = 2000 | title = Speculations on the origin and evolution of the genus ''Leishmania'' | journal = Mem Inst Oswaldo Cruz | volume = 95 | issue = 4| pages = 583–588 | doi=10.1590/s0074-02762000000400023 | pmid=10904419| doi-access = free }}</ref> The ''Euleishmania'' included species currently placed in the subgenera ''Leishmania'', ''Sauroleishmania'', ''Mundinia'' and ''Viannia''. The proposed ''Paraleishmania'' included species of ''Endotypanum,'' ''Leishmamnia''-''L. colomubensis'', ''L. herreri'', ''L. hertigi''and ''L. deanei'' and ''L. equatorensis''. In a recent revision these species were given different generic status.
 
Four subgenera of ''Leishmania'' are now recognised - ''Leishmania'', ''Sauroleishmania'', ''Viannia'' and ''Mundinia'' (the ''L. enriettii'' complex). The genus ''Endotrypanum'' and ''Porcisia'' belong to the ''Paraleishmania''.

There are four ''Mundinia'' species - ''L. (Mundinia) enriettii'',  ''L. (Mundinia) martiniquensis'', ''L. (Mundinia) macropodum'', and ''L. (Mundinia) orientalis,'' which is found in Thailand.<ref name="Jariyapan2018">{{cite journal | last1 = Jariyapan | first1 = N | last2 = Daroontum | first2 = T | last3 = Jaiwong | first3 = K | last4 = Chanmol | first4 = W | last5 = Intakhan | first5 = N | last6 = Sor-Suwan | first6 = S | last7 = Siriyasatien | first7 = P | last8 = Somboon | first8 = P | last9 = Bates | first9 = MD | last10 = Bates | first10 = PA | year = 2018 | title = ''Leishmania (Mundinia) orientalis'' n. sp. (Trypanosomatidae), a parasite from Thailand responsible for localised cutaneous leishmaniasis | journal = Parasit Vectors | volume = 11 | issue = 1| page = 351 | doi = 10.1186/s13071-018-2908-3 | pmid = 29914526 | pmc = 6006788 | doi-access = free }}</ref>

''L. archibaldi'''s specific status is unsettled but it is closely related to ''L. donovani''.
 
''L. herreri'' belongs to the genus ''Endotypanum'' rather than to ''Leishmania''.

''L. donovani'' and ''L. infantum'' are closely related.

===Notes===

The selenoenzyme ''Seltryp'' appears to be unique to this order.<ref name=Mariana2016>{{cite journal|first1=Mariana|last1=Bonilla|first2=Erika|last2=Krull|first3=Florencia|last3=Irigoín|first4=Gustavo|last4=Salinas|title=Selenoproteins of African trypanosomes are dispensable for parasite survival in a mammalian host|journal=Molecular and Biochemical Parasitology|pages=13–19|volume=206|issue=1–2|doi=10.1016/j.molbiopara.2016.03.002|pmid=26975431|first5=Marcelo A.|last5=Comini|year=2016}}</ref> It has been removed from the subgenus ''Viannia''.

''L. deanei'' and ''L. hertigi'', both of which infect porcupines have been moved to the genus ''Porcisia.''

==Classification==

Subgenus '''Leishmania''' {{small|Ross, 1903 sensu Saf'janova, 1982}}
*''[[Leishmania aethiopica]]'' {{small|Bray, Ashford & Bray, 1973}}
*''[[Leishmania amazonensi]]s'' {{small|Lainson & Shaw, 1972}} (includes ''garnhami'' {{small|Scorza et al., 1979}})
*''[[Leishmania arabica]]'' {{small|Peters, Elbihari & Evans, 1986}}
*''[[Leishmania aristidesi]]'' {{small|Lainson & Shaw, 1979}}
*''[[Leishmania donovani]]''{{small| (Laveran & Mesnil, 1903)}}
*''[[Leishmania forattinii]]''{{small| Yoshida, Cuba, Pacheco, Cupolillo, Tavares, Machado, Homen & Grimaldi, 1993}}
*''[[Leishmania gerbilli]]''{{small| Wang, Qu & Guan, 1964}}
*''[[Leishmania infantum]]'' {{small|Nicolle, 1908}} (subspecies ''chagasi'' {{small|Cunha & Chagas, 1937}})
*''[[Leishmania killicki]]'' {{small|Rioux, Lamotte & Pratlong, 1986}}
*''[[Leishmania major]]'' {{small|Yakimoff & Schokhor, 1914}}
*''[[Leishmania mexicana]]'' {{small|Biagi, 1953}}
*''[[Leishmania pifanoi]]'' {{small|Medina & Romero, 1959}}
*''[[Leishmania tropica]]'' {{small|(Wright, 1903)}}
*''[[Leishmania turanica]]'' {{small|Strelkova, Shurkhal, Kellina, Eliseev, Evans, Peters, Chapman, Le Blancq & van Eys, 1990}}
*''[[Leishmania venezeulensis]]'' {{small|Bonfante-Garrido, 1980}}
*''[[Leishmania waltoni]]'' {{small|Shaw, Pratlong & Dedet 2015}}

Subgenus '''[[Mundinia]]''' {{small|Shaw,Camargo and Teixeira 2016}}
*''[[Leishmania enriettii]]'' {{small|Muniz & Medina, 1948}}
*''[[Leishmania macropodum]]'' {{small|Barratt, Kaufer, Peters, Craig, Lawrence, Roberts, Lee, McAuliffe, Stark, Ellis, 2017}}
*''[[Leishmania martiniquensis]]'' {{small|Desbois, Pratlong, Quist and Dedet,2014}}<ref name="DesboisPratlong2014">{{cite journal|last1=Desbois|first1=Nicole|last2=Pratlong|first2=Francine|last3=Quist|first3=Danièle|last4=Dedet|first4=Jean-Pierre|title=''Leishmania (Leishmania) martiniquensis'' n. sp. (Kinetoplastida: Trypanosomatidae), description of the parasite responsible for cutaneous leishmaniasis in Martinique Island (French West Indies)|journal=Parasite|volume=21|year=2014|pages=12|issn=1776-1042|doi=10.1051/parasite/2014011| pmid = 24626346 |pmc = 3952653}} {{open access}}</ref>
*''[[Leishmania orientalis]]''{{small| Jariyapan, Daroontum, Jaiwong, Chanmol,.Intakhan, Sor-Suwan, Siriyasatien, Somboon, Bates, Bates, 2018}}

Subgenus '''[[Sauroleishmania]]''' {{small|Ranque, 1973 sensu Saf'janova, 1982}}
*''[[Leishmania adleri]]'' {{small|Heisch, 1958}}
*''[[Leishmania agamae]]'' {{small|David, 1929}}
*''[[Leishmania ceramodactyli]]'' {{small|Adler & Theodor, 1929}}
*''[[Leishmania gulikae]]'' {{small|Ovezmukhammedov & Saf'janova, 1987}}
*''[[Leishmania gymnodactyli]]'' † {{small|Khodukin & Sofiev, 1940}}
*''[[Leishmania helioscopi]]'' † {{small|Chodukin & Sofiev, 1940}} 
*''[[Leishmania hemidactyli]]'' {{small|Mackie, Gupta & Swaminath, 1923}}
*''[[Leishmania hoogstraali]]'' {{small|McMillan, 1965}}
*''[[Leishmania nicollei]]'' {{small |Chodukin & Sofieff, 1940}}
*''[[Leishmania platycephala]]'' {{small|Telford, 2009}}
*''[[Leishmania phrynocephali]]'' {{small|Chodukin & Sofieff, 1940}}
*''[[Leishmania senegalensis]]'' {{small|Ranque, 1973}}
*''[[Leishmania sofieffi]]'' ↑ {{small|Markov, Lukina & Markova, 1964}}
*''[[Leishmania tarentolae]]'' {{small|Wenyon, 1921}}
*''[[Leishmania zmeevi]]'' ↑ {{small|Andruchko & Markov 1955}}
*''[[Leishmania zuckermani]]'' {{small|Paperna, Boulard, Hering-Hagenbeck & Landau, 2001}}
{{small|↑ Species described as ''Sauroleishmania''. Their development is not like other members of the subgenus and so their taxonomic position is doubtful.}}

Subgenus '''[[Viannia]]''' {{small|Lainson & Shaw 1987}}
*''[[Leishmania braziliensis]]'' {{small|Vianna, 1911}} 
*''[[Leishmania guyanensis]]'' {{small|Floch, 1954}}
*''[[Leishmania lainsoni]]'' {{small|Silveira, Shaw, Braga & Ishikawa, 1987}}
*''[[Leishmania lindenbergi]]'' {{small|Silveira, Ishikawa, De Souza & Lainson, 2002}}
*''[[Leishmania naiffi]]'' {{small|Lainson & Shaw, 1989}}
*''[[Leishmania panamensis]]'' {{small|Lainson & Shaw, 1972}}
*''[[Leishmania peruviana]]'' {{small|Velez, 1913}}
*''[[Leishmania shawi]]'' {{small|Lainson, Braga & de Souza, 1989}}
*''[[Leishmania utingensis]]'' {{small|Braga, Lainson, Ishikawa & Shaw 2003}}

===Related genera===

The relationships between ''Leishmania'' and other genera such as ''Endotrypanum'', ''[[Novymonas]]'', ''Porcisia'', and ''Zelonia'' is presently unclear as they are closely related.<ref>{{Cite journal |last1=Espinosa |first1=O. A. |last2=Serrano |first2=M. G. |last3=Camargo |first3=E. P. |last4=Teixeira |first4=M. M. G. |last5=Shaw |first5=J. J. |date=2018 |title=An appraisal of the taxonomy and nomenclature of trypanosomatids presently classified as Leishmania and Endotrypanum |url=https://pubmed.ncbi.nlm.nih.gov/27976601 |journal=Parasitology |volume=145 |issue=4 |pages=430–442 |doi=10.1017/S0031182016002092 |issn=1469-8161 |pmid=27976601|s2cid=41544524 }}</ref><ref name=":0">{{Cite journal |last1=Mathison |first1=Blaine A. |last2=Bradbury |first2=Richard S. |last3=Pritt |first3=Bobbi S. |date=2021 |title=Medical Parasitology Taxonomy Update, January 2018 to May 2020 |journal=Journal of Clinical Microbiology |volume=59 |issue=2 |pages=e01308–20 |doi=10.1128/JCM.01308-20 |issn=1098-660X |pmc=8111142 |pmid=33028601}}</ref> ''Endotrypanum colombiensis'', ofter known as ''Leishmania colombiensis,'' has been associated with both cutaneous and visceral leishmaniasis in Venezuela.<ref>{{Cite journal |last1=Rodriguez-Bonfante |first1=Claudina |last2=Bonfante-Garrido |first2=Rafael |last3=Grimaldi |first3=Gabriel |last4=Momen |first4=Hooman |last5=Cupolillo |first5=Elisa |date=2003 |title=Genotypically distinct Leishmania colombiensis isolates from Venezuela cause both cutaneous and visceral leishmaniasis in humans |url=https://pubmed.ncbi.nlm.nih.gov/12809806 |journal=Infection, Genetics and Evolution: Journal of Molecular Epidemiology and Evolutionary Genetics in Infectious Diseases |volume=3 |issue=2 |pages=119–124 |doi=10.1016/s1567-1348(03)00012-1 |issn=1567-1348 |pmid=12809806}}</ref>

Genus '''Endotrypanum'''
*''Endotrypanum colombiensis'' {{small|Kreutzer, Corredor, Grimaldi, Grogl, Rowton, Young, Morales, McMahon-Pratt, Guzman & Tesh, 1991}}
*''Endotrypanum equatorensis'' {{small|Grimaldi, Kreutzer, Hashiguchi, Gomet, Mimory & Tesh, 1992}}
*''Endotrypanum herreri'' {{small|Zeledon, Ponce & Murillo, 1979}}
*''Endotrypanum monterogeii'' {{small|Shaw, 1969}}
*''Endotrypanum schaudinni'' {{small|Mesnil and Brimont, 1908}}

Genus '''Novymonas''' {{small|Kostygov and Yurchenko 2016}} 
*''Novymonas esmeraldas'' {{small|Votýpka, Kostygov, Maslov and Lukeš,  2016}}

Genus '''Porcisia''' {{small|Shaw, Camargo and Teixeira, 2016}}
*''Porcisia deanei'' {{small|Lainson & Shaw, 1977}}
*''Porcisia hertigi'' {{small|Herrer, 1971}}

Genus '''Zelonia''' {{small|Shaw, Camargo and Teixeira, 2016}}
*''Zelonia australiensis'' {{small|Barratt, Kaufer, Peters, Craig, Lawrence, Roberts, Lee, McAuliffe, Stark, Ellis, 2017}}
*''Zelonia costaricensis'' {{small|Yurchenko, Lukes, Jirku, Zeledon, Maslov, 2006}}

==Biochemistry and cell biology==
The biochemistry and cell biology of ''Leishmania'' is similar to that of other [[Kinetoplastida|kinetoplastids]]. They share the same main morphological features: a single [[flagellum]] which has an invagination - the flagellar pocket - at its base; a [[kinetoplast]], which is found in the single [[mitochondrion]]; and a subpelicular array of microtubules, which make up the main part of the [[cytoskeleton]].

===Lipophosphoglycan coat===
''Leishmania'' possesses a [[lipophosphoglycan]] coat over the outside of the cell. Lipophosphoglycan is a trigger for [[TLR 2|toll-like receptor 2]], a signalling receptor involved in triggering an [[innate immune system|innate immune response]] in mammals.

The precise structure of lipophosphoglycan varies depending on the species and [[Biological life cycle|lifecycle]] stage of the parasite. The glycan component is particularly variable and different lipophosphoglycan variants can be used as a [[molecular marker]] for different lifecycle stages. [[Lectin]]s, a group of [[proteins]] which bind different glycans, are often used to detect these lipophosphoglycan variants. For example, [[peanut agglutinin]] binds a particular lipophosphoglycan found on the surface of the infective form of ''L. major''.

Lipophosphoglycan is used by the parasite to promote its survival in the host and the mechanisms by which the parasite does this center around modulating the immune response of the host. This is vital, as the ''Leishmania'' parasites live within [[macrophages]] and need to prevent the macrophages from killing them. Lipophosphoglycan has a role in resisting the [[complement system]], inhibiting the [[oxidative burst]] response, inducing an [[inflammation]] response and preventing [[Natural Killer T cell|natural killer T cells]] recognising that the macrophage is infected with the ''Leishmania'' parasite.

{| class="wikitable"
|-
! Type
! Pathogen
! Location
|-
| ''[[Cutaneous leishmaniasis]]'' (localised and diffuse) infections appear as obvious skin reactions.
| The most common is the ''Oriental Sore'' (caused by Old World species ''[[Leishmania major|L. major]]'', ''[[Leishmania tropica|L. tropica]]'', and ''[[Leishmania aethiopica|L. aethiopica]]'').  In the New World, the most common culprits is ''[[Leishmania mexicana|L. mexicana]]''.
| Cutaneous infections are most common in [[Afghanistan]], [[Brazil]], [[Iran]], [[Peru]], [[Saudi Arabia]] and [[Syria]].
|-
| ''[[Mucocutaneous leishmaniasis]]'' <!-- (Espundia or Uta) --> infections start off as a reaction at the bite, and can go by [[metastasis]] into the mucous membrane and become fatal.
| ''[[Leishmania braziliensis|L. braziliensis]]''
| Mucocutaneous infections are most common in [[Bolivia]], [[Brazil]] and [[Peru]]. Mucocutaneous infections are also found in [[Karamay]], China Xinjiang Uygur Autonomous Region.
|-
| ''[[Visceral leishmaniasis]]'' infections are often recognised by fever, swelling of the liver and spleen, and [[anemia]].  They are known by many local names, of which the most common is probably ''[[kala azar]]'',<ref name=humber>[http://homepages.uel.ac.uk/D.P.Humber/akhter/dis.htm Visceral leishmniasis: The disease] {{webarchive|url=https://web.archive.org/web/20050428075129/http://homepages.uel.ac.uk/D.P.Humber/akhter/dis.htm |date=2005-04-28 }}</ref><ref name=bartleby>[http://www.bartleby.com/61/51/K0005100.html kala-azar] {{webarchive|url=https://web.archive.org/web/20090210143548/http://www.bartleby.com/61/51/K0005100.html |date=2009-02-10 }}. The American Heritage Dictionary of the English Language</ref>
| Caused exclusively by species of the ''L. donovani'' complex (''[[Leishmania donovani|L. donovani]]'', ''[[Leishmania infantum|L. infantum]]'' syn. ''L. chagasi'').<ref name=Sherris />
| Found in tropical and subtropical areas of all continents except [[Australia]], visceral infections are most common in [[Bangladesh]], [[Brazil]], [[India]], [[Nepal]], and [[Sudan]].<ref name=Sherris /> Visceral leishmaniasis also found in part of China, such as Sichuan Province, Gansu Province, and Xinjiang Uygur Autonomous Region.
|}

===Intracellular mechanism of infection===
In order to avoid destruction by the [[immune system]] and thrive, the ''Leishmania'' 'hides' inside its host's cells. This location enables it to avoid the action of the [[humoral immune response]] (because the pathogen is safely inside a cell and outside the open bloodstream), and furthermore it may prevent the immune system from destroying its host through nondanger surface signals which discourage [[apoptosis]]. The primary cell types ''Leishmania'' infiltrates are [[phagocytosis|phagocytotic]] cells such as [[neutrophils]] and [[macrophages]].<ref>{{cite journal|last=Vannier-Santos|first=MA|author2=Martiny A |author3=de Souza W.|title=Cell biology of Leishmania spp.: invading and evading.|journal=Current Pharmaceutical Design|date=August 2002|pages=297–318|pmid=11860368|volume=8|issue=4|doi=10.2174/1381612023396230}}</ref>

Usually, a phagocytotic immune cell like a macrophage will ingest a pathogen within an enclosed [[endosome]] and then fill this endosome with enzymes which digest the pathogen. However, in the case of ''Leishmania'', these enzymes have no effect, allowing the parasite to multiply rapidly. This uninhibited growth of parasites eventually overwhelms the host macrophage or other immune cell, causing it to die.<ref>{{cite journal|last=Paul|first=William E.|title=Infectious Diseases and the Immune System|journal=Scientific American|volume=269|issue=3|date=September 1993|pages=94–95|bibcode=1993SciAm.269c..90P|doi=10.1038/scientificamerican0993-90|pmid=8211095}}</ref>

Transmitted by the [[sandfly]], the [[protozoan]] [[parasitism|parasites]] of ''L. major'' may switch the strategy of the first immune defense from eating/inflammation/killing to eating/no inflammation/no killing of their host [[phagocyte]] and corrupt it for their own benefit.{{Citation needed|date=December 2008}} They use the willingly phagocytosing polymorphonuclear neutrophil granulocytes (PMNs) rigorously as a tricky hideout, where they [[cell growth|proliferate]] unrecognized from the immune system and enter the long-lived [[macrophages]] to establish a "hidden" [[infection]].{{Citation needed|date=December 2008}}

===Uptake and survival===
[[File:Leishmaniasis life cycle diagram en.svg|thumb|579px|center|Lifecycle of ''Leishmania'']]

Upon [[microbial]] infection, PMNs move out from the bloodstream through the vessels' endothelial layer, to the site of the infected tissue (dermal tissue after fly bite). They immediately initiate the first immune response and phagocytize the invader by recognition of foreign and activating surfaces on the parasite. Activated PMN secrete [[chemokines]], [[Interleukin 8|IL-8]] particularly, to attract further [[granulocytes]] and stimulate phagocytosis. Further, ''L. major'' increases the secretion of IL-8 by PMNs. This mechanism is observed during infection with other [[obligate intracellular parasites]], as well. For microbes like these, multiple intracellular survival mechanisms exist. Surprisingly, the coinjection of apoptotic and viable pathogens causes by far a more fulminate course of disease than injection of only viable parasites. When the anti-inflammatory signal [[phosphatidylserine]] usually found on apoptotic cells, is exposed on the surface of dead parasites, ''L. major'' switches off the [[oxidative burst]], thereby preventing killing and degradation of the viable pathogen.

In the case of ''Leishmania'', progeny are not generated in PMNs, but in this way they can survive and persist untangled in the primary site of infection. The promastigote forms also release ''Leishmania'' chemotactic factor (LCF) to actively recruit neutrophils, but not other [[leukocytes]], for instance [[monocytes]] or [[NK cells]]. In addition to that, the production of [[interferon gamma]] (IFNγ)-inducible protein 10 (IP10) by PMNs is blocked in attendance of ''Leishmania'', what involves the shut down of inflammatory and protective immune response by NK and [[Th1 cell]] recruitment. The pathogens stay viable during phagocytosis since their primary hosts, the PMNs, expose apoptotic cell-associated molecular pattern (ACAMP) signaling "no pathogen".

===Persistency and attraction===
The lifespan of [[neutrophil granulocytes]] is quite short. They circulate in [[bloodstream]] for about 6 to 10 hours after leaving [[bone marrow]], whereupon they undergo spontaneous [[apoptosis]]. Microbial pathogens have been reported to influence cellular apoptosis by different strategies. Obviously because of the inhibition of [[caspase]]3-activation, ''L. major'' can induce the delay of neutrophils apoptosis and extend their lifespan for at least 2–3 days. The fact of extended lifespan is very beneficial for the development of infection because the final host cells for these parasites are macrophages, which normally migrate to the sites of infection within two or three days. The pathogens are not dronish; instead they take over the command at the primary site of infection. They induce the production by PMNs of the chemokines MIP-1α and MIP-1β ([[macrophage inflammatory protein]]) to recruit macrophages.<ref>{{cite journal |last1=Laskay |first1=Tamás |last2=van Zandbergen |first2=Ger |last3=Solbach |first3=Werner |title=Neutrophil granulocytes – Trojan horses for Leishmania major and other intracellular microbes? |journal=Trends in Microbiology |date=May 2003 |volume=11 |issue=5 |pages=210–214 |doi=10.1016/S0966-842X(03)00075-1}}</ref>

An important factor in prolonging infection is the inhibition of [[Adaptive immune system|the adaptive immune system]]. This occurs especially during the intercellular phases, when amastigotes search for new macrophages to infect and are more susceptible to immune responses. Nearly all types of [[phagocyte]]s are targeted.<ref>{{cite journal |last1=Martínez-López |first1=María |last2=Soto |first2=Manuel |last3=Iborra |first3=Salvador |last4=Sancho |first4=David |title=Leishmania Hijacks Myeloid Cells for Immune Escape |journal=Frontiers in Microbiology |date=7 May 2018 |volume=9 |doi=10.3389/fmicb.2018.00883 | pmid = 29867798 | pmc= 5949370 | doi-access= free }}</ref> For example, [[Mincle receptor|mincle]] has been shown to be targeted by ''L. major''. Interaction between mincle and a protein released by the parasite results in a weakened immune response in [[dendritic cell]]s.<ref>{{cite journal |last1=Iborra |first1=Salvador |last2=Martínez-López |first2=María |last3=Cueto |first3=Francisco J. |last4=Conde-Garrosa |first4=Ruth |last5=Del Fresno |first5=Carlos |last6=Izquierdo |first6=Helena M. |last7=Abram |first7=Clare L. |last8=Mori |first8=Daiki |last9=Campos-Martín |first9=Yolanda |last10=Reguera |first10=Rosa María |last11=Kemp |first11=Benjamin |last12=Yamasaki |first12=Sho |last13=Robinson |first13=Matthew J. |last14=Soto |first14=Manuel |last15=Lowell |first15=Clifford A. |date=October 2016 |title=Leishmania Uses Mincle to Target an Inhibitory ITAM Signaling Pathway in Dendritic Cells that Dampens Adaptive Immunity to Infection |journal=Immunity |volume=45 |issue=4 |pages=788–801 |doi=10.1016/j.immuni.2016.09.012 |pmc=5074365 |pmid=27742545 |last16=Sancho |first16=David}}</ref>

=== Silent phagocytosis theory ===
To save the integrity of the surrounding tissue from the [[toxic]] cell components and [[proteolysis|proteolytic]] [[enzyme]]s contained in neutrophils, the apoptotic PMNs are silently cleared by macrophages. Dying PMNs expose the "eat me"-signal [[phosphatidylserine]] which is transferred to the outer leaflet of the [[plasma membrane]] during apoptosis. By reason of delayed apoptosis, the parasites that persist in PMNs are taken up into macrophages, employing an absolutely [[physiology|physiological]] and nonphlogistic process. The strategy of this "silent phagocytosis" has the following advantages for the parasite:

* Taking up apoptotic cells silences macrophage killing activity leading to a survival of the pathogens.
* Pathogens inside of PMNs have no direct contact to the macrophage surface [[Receptor (biochemistry)|receptors]], because they can not see the parasite inside the apoptotic cell. So, the activation of the phagocyte for immune activation does not occur.

However, studies have shown this is unlikely, as the pathogens are seen to leave apoptopic cells and no evidence is known of macrophage uptake by this method.

== Molecular biology ==
An important aspect of the ''Leishmania'' protozoan is its [[glycoconjugate]] layer of [[lipophosphoglycan]] (LPG).  This is held together with a phosphoinositide membrane anchor, and has a tripartite structure consisting of a lipid domain, a neutral hexasaccharide, and a phosphorylated galactose-mannose, with a termination in a neutral cap.  Not only do these parasites develop postphlebotomus digestion, but it is also thought to be essential to oxidative bursts, thus allowing passage for infection. Characteristics of intracellular digestion include an [[endosome]] fusing with a [[lysosome]], releasing acid [[hydrolase]]s which degrade [[DNA]], [[RNA]], proteins and [[carbohydrates]].

== Genomics ==
[[File:Leishmania tropica 7.jpg|thumb|right|250px|''[[Leishmania tropica]]'']]

The genomes of four ''Leishmania'' species (''L. major'', ''L. infantum'', ''L. donovani'' and ''L. braziliensis'') have been sequenced, revealing more than 8300 protein-coding and 900 [[RNA]] genes. Almost 40% of protein-coding genes fall into 662 families containing between two and 500 members. Most of the smaller gene families are tandem arrays of one to three genes, while the larger gene families are often dispersed in tandem arrays at different [[Locus (genetics)|loci]] throughout the [[genome]].  Each of the 35 or 36 [[chromosome]]s is organized into a small number of gene clusters of tens-to-hundreds of genes on the same DNA strand.  These clusters can be organized in head-to-head (divergent) or tail-to-tail (convergent) fashion, with the latter often separated by [[tRNA]], [[rRNA]] and/or [[snRNA]] genes.  Transcription of protein-coding genes initiates bidirectionally in the divergent strand-switch regions between gene clusters and extends poly[[cistron]]ically through each gene cluster before terminating in the strand-switch region separating convergent clusters.  ''Leishmania'' [[telomere]]s are usually relatively small, consisting of a few different types of repeat sequence.  Evidence can be found for recombination between several different groups of telomeres.  The ''L. major'' and ''L. infantum'' genomes contain only about 50 copies of inactive degenerated ''Ingi''/L1Tc-related elements (DIREs), while ''L. braziliensis'' also contains several telomere-associated transposable elements and spliced leader-associated retroelements.  The ''Leishmania'' genomes share a conserved core proteome of about 6200 genes with the related trypanosomatids ''Trypanosoma brucei'' and ''Trypanosoma cruzi'', but around 1000 ''Leishmania''-specific genes are known, which are mostly randomly distributed throughout the genome.  Relatively few (about 200) species-specific differences in gene content exist between the three sequenced ''Leishmania'' genomes, but about 8% of the genes appear to be evolving at different rates between the three species, indicative of different selective pressures that could be related to disease pathology.  About 65% of protein-coding genes currently lack functional assignment.<ref name=MylerP/>

''Leishmania'' species produce several different [[heat shock protein]]s. These include Hsp83, a homolog of [[Hsp90]]. A regulatory element in the [[3' UTR]] of Hsp83 controls [[Translation (genetics)|translation]] of Hsp83 in a temperature-sensitive manner. This region forms a stable [[Nucleic acid secondary structure|RNA structure]] which melts at higher temperatures.<ref>{{cite journal|last=David|first=M|author2=Gabdank, I |author3=Ben-David, M |author4=Zilka, A |author5=Orr, I |author6=Barash, D |author7= Shapira, M |title=Preferential translation of Hsp83 in Leishmania requires a thermosensitive polypyrimidine-rich element in the 3' UTR and involves scanning of the 5' UTR.|journal=RNA|date=February 2010|volume=16|issue=2|pages=364–74|pmid=20040590|doi=10.1261/rna.1874710|pmc=2811665}}</ref>

== Genomic instability ==

''Leishmania'' lacks of promoter-dependent regulation, so its genomic regulation is at post-transcriptional level through [[Copy number variation|copy number variations (CNV)]] of transcripts, a mechanism capable of controlling the abundance of these transcripts according to the situation in which the organism finds itself. These processes cause a great susceptibility to genomic instability in the parasite. This involves [[Epistasis|epistatic interactions]] between genes, which drive these changes in gene expression, leading to compensatory mechanisms in the ''Leishmania'' genome that result in the adaptive evolution of the parasite.
During the research carried out by Giovanni Bussotti and collaborators at the Pasteur Institute, belonging to the University of Paris, a genome-wide association study ([[Genome-wide association study|GWAS]]) of ''Leishmania donovani'' identified CNVs in 14% of the coding regions and in 4% of the non-coding regions. In addition, an [[Experimental evolution|experimental evolution study (EE Approach)]] was performed on L. donovani amastigotes obtained from clinical cases of hamsters. By extracting these amastigotes from infected organisms and culturing them in vitro for 36 weeks (3800 generations), it was demonstrated how genomic instability in this parasite is capable of adapting to complicated situations, such as in vitro culture.
An 11kb deletion was detected in the gene coding for Ld1S_360735700, a [[NIMA-related kinase 1|NIMA-related kinase]] with key functions in the correct progression of mitosis. With the advancement of in vitro culture generations the loss of the kinase becomes more notorious, decreasing growth rate of the parasite, but the genomic instability of Leishmania manages, through compensatory mechanisms, to attenuate this reduction in growth so that the in vitro culture is maintained. First, as an adaptation of the culture to the loss of this kinase, it was detected an increase in the expression of another orthologous kinase (Ld1S_360735800) whose coding region is adjacent to that of the lost kinase. Secondly, a reduction in the expression of 23 transcripts related to [[Flagellum|flagellar biogenesis]] was observed. So adaptation in Leishmania leads the parasite to eliminate flagellar movement from its needs, since it is not necessary in in vitro culture, preserving the energy invested in this movement to increase the growth rate and compensating the loss of the kinase.
Finally, coamplification of ribosomal protein clusters, [[ribosomal RNA]] (rRNA), [[transfer RNA]] (tRNA) and [[SnoRNA|nucleolar small RNA]] (snoRNA) was observed. Increased expression of these clusters leads to increased ribosomal biogenesis and protein biosynthesis. This is most evident in the case of small nucleolar RNAs (snoRNA), for which amplification of a large cluster of 15 snoRNAs was observed on chromosome 33. The function of these nucleic acids is [[methylation]] and inclusion of [[Pseudouridine|pseuouridine]] in ribosomes. In this case, an increase in these modifications was observed in the large subunits of the ribosomes of individuals in culture, specifically in the PTC ([[peptidyl transferase]] center) and in the mRNA entry tunnel to the ribosome for protein synthesis. These changes lead to an increase in ribosomal biogenesis, resulting in increased protein synthesis and growth rate.
In conclusion, the loss of the kinase is compensated by the genomic instability of ''Leishmania donovani'' by increasing the expression of another orthologous kinase, decreasing flagellar biogenesis and increasing ribosomal biogenesis. These compensations result in the growth rate of the culture being as less affected as possible by the initial loss of the kinase, and the parasite is perfectly adapted to the in vitro culture, which is not its natural habitat.
<ref>{{cite journal |last1=Bussotti |first1=Giovanni |last2=Piel |first2=Laura |last3=Pescher |first3=Pascale |last4=Domagalska |first4=Malgorzata A. |last5=Rajan |first5=K. Shanmugha |last6=Cohen-Chalamish |first6=Smadar |last7=Doniger |first7=Tirza |last8=Hiregange |first8=Disha-Gajanan |last9=Myler |first9=Peter J. |last10=Unger |first10=Ron |last11=Michaeli |first11=Shulamit |last12=Späth |first12=Gerald F. |title=Genome instability drives epistatic adaptation in the human pathogen Leishmania |journal=Proceedings of the National Academy of Sciences |date=21 December 2021 |volume=118 |issue=51 |pages=e2113744118 |doi=10.1073/pnas.2113744118 |pmid=34903666 |pmc=8713814 |bibcode=2021PNAS..11813744B |language=en |issn=0027-8424|doi-access=free }}</ref>

== Sexual reproduction ==

A microbial pathogen's reproductive system is one of the basic biologic processes that condition the microorganism's ecology and disease spread.<ref name="pmid20808896">{{cite journal |last1=Rougeron |first1=Virginie |last2=De Meeûs |first2=Thierry |last3=Kako Ouraga |first3=Sandrine |last4=Hide |first4=Mallorie |last5=Bañuls |first5=Anne-Laure |title=“Everything You Always Wanted to Know about Sex (but Were Afraid to Ask)” in Leishmania after Two Decades of Laboratory and Field Analyses |journal=PLoS Pathogens |date=19 August 2010 |volume=6 |issue=8 |pages=e1001004 |doi=10.1371/journal.ppat.1001004 |pmid=20808896 |pmc=2924324 |doi-access=free }}</ref> In 2009 Akopyants et al.<ref name="pmid19359589">{{cite journal |last1=Akopyants |first1=Natalia S. |last2=Kimblin |first2=Nicola |last3=Secundino |first3=Nagila |last4=Patrick |first4=Rachel |last5=Peters |first5=Nathan |last6=Lawyer |first6=Phillip |last7=Dobson |first7=Deborah E. |last8=Beverley |first8=Stephen M. |last9=Sacks |first9=David L. |title=Demonstration of Genetic Exchange During Cyclical Development of Leishmania in the Sand Fly Vector |journal=Science |date=10 April 2009 |volume=324 |issue=5924 |pages=265–268 |doi=10.1126/science.1169464 |pmid=19359589 |pmc=2729066 |bibcode=2009Sci...324..265A }}</ref> demonstrated that ''L. major'' has a sexual cycle, including a meiotic process.  Hybrid progeny are formed that have full genomic complements from both parents.  Mating only occurs in the [[sand fly]] vector, and hybrids can be transmitted to the mammalian host by sand fly bite.  In ''L. braziliensis'' matings in nature are predominantly between related individuals resulting in extreme inbreeding.<ref name="pmid19497885">{{cite journal |last1=Rougeron |first1=Virginie |last2=De Meeûs |first2=Thierry |last3=Hide |first3=Mallorie |last4=Waleckx |first4=Etienne |last5=Bermudez |first5=Herman |last6=Arevalo |first6=Jorge |last7=Llanos-Cuentas |first7=Alejandro |last8=Dujardin |first8=Jean-Claude |last9=De Doncker |first9=Simone |last10=Le Ray |first10=Dominique |last11=Ayala |first11=Francisco J. |last12=Bañuls |first12=Anne-Laure |title=Extreme inbreeding in Leishmania braziliensis |journal=Proceedings of the National Academy of Sciences |date=23 June 2009 |volume=106 |issue=25 |pages=10224–10229 |doi=10.1073/pnas.0904420106 |pmid=19497885 |pmc=2700931  |bibcode=2009PNAS..10610224R |doi-access=free }}</ref>  The rate of outcrossing between different strains of ''Leishmania'' in the sand fly vector depends on the frequency of co-infection.  Such outcrossing events appear to be rare in ''L. major'' <ref name="pmid19359589" /> and ''L. donovani''.<ref name="pmid24453988">{{cite journal |last1=Rogers |first1=Matthew B. |last2=Downing |first2=Tim |last3=Smith |first3=Barbara A. |last4=Imamura |first4=Hideo |last5=Sanders |first5=Mandy |last6=Svobodova |first6=Milena |last7=Volf |first7=Petr |last8=Berriman |first8=Matthew |last9=Cotton |first9=James A. |last10=Smith |first10=Deborah F. |title=Genomic Confirmation of Hybridisation and Recent Inbreeding in a Vector-Isolated Leishmania Population |journal=PLoS Genetics |date=16 January 2014 |volume=10 |issue=1 |pages=e1004092 |doi=10.1371/journal.pgen.1004092 |pmid=24453988 |pmc=3894156 |doi-access=free }}</ref>

''L. infantum'' produces proteins BRCA1 and RAD51 that interact with each other to promote homologous recombinational repair.<ref name="pmid22505581">{{cite journal |last1=Genois |first1=Marie-Michelle |last2=Mukherjee |first2=Angana |last3=Ubeda |first3=Jean-Michel |last4=Buisson |first4=Rémi |last5=Paquet |first5=Eric |last6=Roy |first6=Gaétan |last7=Plourde |first7=Marie |last8=Coulombe |first8=Yan |last9=Ouellette |first9=Marc |last10=Masson |first10=Jean-Yves |title=Interactions between BRCA2 and RAD51 for promoting homologous recombination in Leishmania infantum |journal=Nucleic Acids Research |date=August 2012 |volume=40 |issue=14 |pages=6570–6584 |doi=10.1093/nar/gks306 |pmid=22505581 |pmc=3413117}}</ref> These proteins play a key role in meiosis.  Thus, meiotic events provide the adaptive advantage of efficient recombinational repair of DNA damages even when they do not lead to outcrossing<ref>{{cite journal |last1=Bernstein |first1=Harris |last2=Byerly |first2=Henry C. |last3=Hopf |first3=Frederic A. |last4=Michod |first4=Richard E. |title=Genetic Damage, Mutation, and the Evolution of Sex |journal=Science |date=20 September 1985 |volume=229 |issue=4719 |pages=1277–1281 |doi=10.1126/science.3898363}}</ref>

== See also ==
* [[Canine leishmaniasis]]
* [[List of parasites (human)]]

== References ==
{{Reflist|30em}}

== Further reading ==
*{{cite journal |doi=10.1073/pnas.0600843103 |pmid=16945916 |pmc=1564231 |title=Leishmania disease development depends on the presence of apoptotic promastigotes in the virulent inoculum |journal=Proceedings of the National Academy of Sciences |volume=103 |issue=37 |pages=13837–42 |year=2006 |last1=Van Zandbergen |first1=G |last2=Bollinger |first2=A |last3=Wenzel |first3=A |last4=Kamhawi |first4=S |last5=Voll |first5=R |last6=Klinger |first6=M |last7=Muller |first7=A |last8=Holscher |first8=C |last9=Herrmann |first9=M |last10=Sacks |first10=D |last11=Solbach |first11=W |last12=Laskay |first12=T |bibcode=2006PNAS..10313837V |doi-access=free }}
*Shaw, Jeffrey Jon (1969). [https://discover.libraryhub.jisc.ac.uk/id/3180107 The Haemoflagellates of Sloths]. [[H. K. Lewis & Co. Ltd.]]: London.
*{{cite journal |last1=Ansari |first1=Md Yousuf |last2=Dikhit |first2=Manas Ranjan |last3=Sahoo |first3=Ganesh Chandra |last4=Das |first4=Pradeep |title=Comparative modeling of HGPRT enzyme of L. donovani and binding affinities of different analogs of GMP |journal=International Journal of Biological Macromolecules |date=April 2012 |volume=50 |issue=3 |pages=637–649 |doi=10.1016/j.ijbiomac.2012.01.010}}

== External links ==
{{Commons category}}
* A discussion list [http://lineu.icb.usp.br/cgi-bin/mailman/listinfo/leish-l (Leish-L)] is also available with over 600 subscribers to the list, ranging from molecular biologists to public health workers, from many countries both inside and outside endemic regions. Comments and questions are welcomed.
* [https://kinetoplastids.biomedcentral.com/ KBD: Kinetoplastid Biology and Disease], is a website devoted to leishmaniasis, sleeping sickness and [[Chagas disease]] (American trypanosomiasis).  It contains free access to full text peer-reviewed articles on these subjects.  The site contains many articles relating to the unique kinetoplastid organelle and genetic material therein.
* [https://www.worldcommunitygrid.org/research/dsfl/overview.s Drug Search for Leishmaniasis] [[World Community Grid]]

{{Excavata}}

{{Taxonbar|from=Q524818}}
{{Authority control}}

[[Category:Parasitic excavates]]
[[Category:Trypanosomatida]]
[[Category:Euglenozoa genera]]