Leishmania 50468 225088453 2008-07-11T20:39:46Z TimVickers 1635280 /* Uptake and survival */ format {{Taxobox | color = khaki | name = ''Leishmania'' | image = Leishmania_donovani_01.png | image_width = 240px | image_caption = ''Leishmania donovani'' in bone marrow cell. | domain = [[Eukaryote|Eukaryota]] | unranked_phylum = [[Excavata]] | phylum = [[Euglenozoa]] | classis = [[Kinetoplastida]] | ordo = [[Trypanosomatida]] | genus = '''''Leishmania''''' | subdivision_ranks = Species | subdivision = ''L. aethiopica''<br /> ''L. amazonensis''<br /> ''L. arabica''<br /> ''L. archibaldi'' (disputed species)<br /> ''L. aristedesi''<br /> ''L. (Viannia) braziliensis''<br /> ''L. chagasi'' (syn. ''L. infantum'')<br /> ''L. (Viannia) colombiensis''<br /> ''L. deanei''<br /> ''L. donovani''<br /> ''L. enriettii''<br /> ''L. equatorensis''<br /> ''L. forattinii''<br /> ''L. garnhami''<br /> ''L. gerbili''<br /> ''L. (Viannia) guyanensis''<br /> ''L. herreri''<br /> ''L. hertigi''<br /> ''L. infantum''<br /> ''L. killicki''<br /> ''L. (Viannia) lainsoni''<br /> ''L. major''<br /> ''L. mexicana''<br /> ''L. (Viannia) naiffi''<br /> ''L. (Viannia) panamensis''<br /> ''L. (Viannia) peruviana''<br /> ''L. (Viannia) pifanoi''<br /> ''L. (Viannia) shawi''<br /> ''L. tarentolae''<br /> ''L. tropica''<br /> ''L. turanica''<br /> ''L. venezuelensis''<br /> }} '''''Leishmania''''' is a [[genus]] of [[trypanosome]] [[protozoa]], and is the [[parasite]] responsible for the disease [[leishmaniasis]].<ref name=Sherris>{{cite book | author = Ryan KJ; Ray CG (editors) | title = Sherris Medical Microbiology | edition = 4th ed. | pages = 749–54 | publisher = McGraw Hill | year = 2004 | isbn = 0838585299 }}</ref><ref name=MylerP>{{cite book | author = Myler P; Fasel N (editors). | title = Leishmania: After The Genome | publisher = Caister Academic Press | year = 2008 | id = ISBN 978-1-904455-28-8 }}</ref> It is spread through [[sandfly|sandflies]] of the genus ''[[Phlebotomus]]'' in the [[Old World]], and of the genus ''[[Lutzomyia]]'' in the [[New World]]. Their primary hosts are [[vertebrate]]s; ''Leishmania'' commonly infects [[hyrax]]es, [[canid]]s, [[rodent]]s, and [[human]]s. ''Leishmania'' currently affects 12 million people in 88 countries. ==Origin== The origins of ''Leishmania'' are unclear.<ref name=Momen_2000>{{cite journal | author = Momen H, Cupolillo E | title = Speculations on the origin and evolution of the genus Leishmania | journal = Mem. Inst. Oswaldo Cruz | volume = 95 | issue = 4 | pages = 583–8 | year = 2000 | pmid = 10904419 | doi = 10.1590/S0074-02762000000400023 <!--Retrieved from CrossRef by DOI bot-->| accessdate = 2007-05-26}}</ref><ref name=Noyes_2000>{{cite journal | author = Noyes HA, Morrison DA, Chance ML, Ellis JT | title = Evidence for a neotropical origin of Leishmania | journal = Mem. Inst. Oswaldo Cruz | volume = 95 | issue = 4 | pages = 575–8 | year = 2000 | pmid = 10904417 | doi = 10.1590/S0074-02762000000400021 <!--Retrieved from CrossRef by DOI bot-->| accessdate = 2007-05-26}}</ref> One possible theory proposes an African origin, with migration to the Americas. Another migration from the Americas to the [[Old World]] about 15 million years ago, across the [[Bering Strait]] land bridge. Another proposes a [[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 = | accessdate = 2007-05-26}}</ref> Such migrations would entail 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]] (there named ''L. chagasi''), since European colonization of the [[New World]], where the parasites picked up its current New World [[Vector (biology)|vectors]] in their respective ecologies. This is the cause of the epidemics now evident. One recent New World epidemic concerns foxhounds in the USA. ==Pathophysiology== ''Leishmania'' cells have two [[Morphology (biology)|morphological]] forms: ''promastigote'' (with an anterior [[flagellum]])<ref name=photo>[http://www.eyeofscience.com/eos2/english/gallery/medizin/bsp5.html# Leishmania mexicana / Leishmania major]</ref> in the insect host, and ''amastigote'' (without flagella) in the vertebrate host. Infections are regarded as cutaneous, mucocutaneous, or visceral. ''Cutaneous'' (localized and diffuse) infections appear as obvious skin reactions. The most common is the ''Oriental Sore'' (caused by Old World species ''L. major'', ''L. tropica'', and ''L. aethiopica''). In the New World, the most common culprits are ''L. mexicana'' and ''L. (Viannia) braziliensis''. Cutaneous infections are most common in [[Afghanistan]], [[Brazil]], [[Iran]], [[Peru]], [[Saudi Arabia]] and [[Syria]]. ''Mucocutaneous'' (espundia) infections will start off as a reaction at the bite, and can go via [[metastasis]] into the mucous membrane and become fatal. Mucocutaneous infections are most common in [[Bolivia]], [[Brazil]] and [[Peru]]. Mucocutaneous infections are also found in [[Karamay]], China Xinjiang Uygur Autonomous Region. ''Visceral'' infections are often recognized 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]</ref><ref name=bartleby>[http://www.bartleby.com/61/51/K0005100.html kala-azar] The American Heritage® Dictionary of the English Language </ref> and are caused exclusively by species of the ''L. donovani'' complex (''L. donovani'', ''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. ==Treatment== {{main|Leishmaniasis}} Antimonial compounds are the traditional treatments for leishmaniasis ([[sodium stibogluconate]], [[meglumine antimoniate]]).<ref>[http://www.icp.ucl.ac.be/~opperd/parasites/leish5.htm Treatment of Leishmaniasis<!-- Bot generated title -->]</ref> Resistance to the antimonials is prevalent in some parts of the world, and the most common alternative is [[amphotericin B]]<ref>www.pdhealth.mil/downloads/Leish_brfng.ppt</ref> (see [[leishmaniasis]] for other treatment options). Paromomycin is an inexpensive alternative with fewer side effects than amphotericin that [[The Institute for OneWorld Health]] has funded for production as an [[orphan drug]] for use in treatment of leishmaniasis, starting in India. ==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 phosphrorylated galactose-mannose, with a termination in a neutral cap. Not only do these parasites develop post-phlebotomus digestion but, it is 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== [[Image:Leishmania tropica 7.jpg|thumb|right|250px|''[[Leishmania tropica]]'']] The genomes of three ''Leishmania'' species (''L. major'', ''L. infantum'' 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 [[loci]] throughout the [[genome]]. Each of the 35 or 36 [[chromosome]]s are 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 bi-directionally 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'' [[telomer]]es 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 ~50 copies of inactive degenerated ''Ingi''/L1Tc-related elements (DIREs), while ''L. braziliensis'' also contains several telomere-associated transposable elements (TATEs) and spliced leader-associated (SLACs) retroelements. The ''Leishmania'' genomes share a conserved core proteome of ~6200 genes with the related trypanosomatids ''Trypanosoma brucei'' and ''Trypanosoma cruzi'' , but there are ~1000 ''Leishmania''-specific genes (LSGs), which are mostly randomly distributed throughout the genome. There are relatively few (~200) species-specific differences in gene content between the three sequenced ''Leishmania'' genomes, but ~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>{{cite book | author = Myler P; Fasel N (editors). | title = Leishmania: After The Genome | publisher = Caister Academic Press | year = 2008 | url=http://www.horizonpress.com/leish | id = [http://www.horizonpress.com/leish ISBN 978-1-904455-28-8 ]}}</ref> == Leishmania as component of CVBD == ''Canine Vector-borne Diseases'' ([[CVBD]]) covers diseases caused by pathogens transmitted by ectoparasites as ticks, fleas, sand flies or mosquitoes. Other microorganism-based diseases caused by ectoparasites include ''[[Bartonella]]'', ''[[Borrelia]]'', '' [[Babesia]]'', Dirofilaria, Ehrlichia, and Anaplasma. ==Neutrophil granulocytes - the Trojan horses for Leishmania parasites== The strategy of the "Trojan horse" as a mechanism of [[pathogenicity]] of [[intracellular]] [[microorganisms]] is, to avoid the [[immune system]] and its memory function cleverly, with [[phagocytosis]] of infected and [[apoptotic]] [[neutrophils]] by [[macrophages]], employing the non-danger surface signals of apoptotic cells. Transmitted by the [[sandfly]], the [[protozoan]] [[parasites]] of the genus ''[[Leishmania 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. They use the willingly phagocytosing polymorphonuclear neutrophil granulocytes (PMN) rigorously as a tricky hideout, where they [[proliferate]] unrecognized from the immune system and enter the long-lived [[macrophages]] to establish a “hidden” [[infection]]. ==Uptake and survival== [[Image:Leishmania LifeCycle.gif|thumb|none|579px|''Leishmania'' life cycle]] By a [[microbial]] infection PMN move out from the bloodstream and through the vessels’ endothelial layer, to the site of the infected tissue (dermal tissue after fly bite). They immediately start their business there as the first immune response and phagocyte the invader because of the foreign and activating surfaces. In that processes an [[inflammation]] emerges. Activated PMN secrete [[chemokines]], [[IL-8]] particularly, to attract further [[granulocytes]] and stimulate them to phagocytosis. Furthermore ''Leishmania major'' increases the secretion of IL-8 by PMN. In the parasites case, that may not sound reasonable at first. We can observe this mechanism on other [[obligate intracellular parasites]], too. For microbes like these, there are several ways to survive inside cells. Surprisingly, the co-injection of apoptotic and viable pathogens causes by far a more fulminate course of disease than injection of only viable parasites. Exposing on the surface of dead parasites the anti-inflammatory signal [[phosphatidylserine]], usually found on apoptotic cells, ''Leishmania major'' switches off the [[oxidative burst]], so killing and degradation of the co-injected viable pathogen is not achieved. In case of ''Leishmania'' progeny is not generated in PMN, but in this way they can survive and persist untangled on the primary site of infection. The [[promastigote]] forms also release LCF (Leishmania chemotactic factor) to recruit actively 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 PMN 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 PMN, 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 or 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 ''Leishmania 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 2 or 3 days. The pathogens are not dronish; instead they take over the command at the primary site of infection. They induce the production by PMN of the chemokines MIP-1α and MIP-1β ([[macrophage inflammatory protein]]) to recruit macrophages. ==Silent phagocytosis== To save the integrity of the surrounding tissue from the [[toxic]] cell components and [[proteolytic]] [[enzymes]] contained in neutrophils, the apoptotic PMN are silently cleared by macrophages. Dying PMN 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 PMN are taken up into macrophages, employing an absolutely [[physiological]] and non-phlogistic process. The strategy of this "'''silent phagocytosis'''" has following advantage for the parasite: • Taking up apoptotic cells silences macrophage killing activity leading to a survival of the pathogens. • Pathogens inside of PMN have no direct contact to the macrophage surface [[receptors]], because they can not see the parasite inside the apoptotic cell. So the activation of the phagocyte for immune activation does not occur. ==Literature:== *Zandbergen et al. "''Leishmania'' disease development depends on the presence of apoptotic promastigotes in the virulent inoculum", PNAS, Sept. 2006 ([http://www.pnas.org/cgi/reprint/103/37/13837.pdf PDF]) *Laskay et al. "Neutrophil granulocytes - Trojan horses for "Leishmania major" and other intracellular microbes?", TRENDS in microbiology, May 2003 *Shaw, J. J. (1969). ''The haemoflagellates of sloths.'' London, H. K. Lewis & Co. Ltd. ([http://old.freedrive.com/public/20445/Shaw_J.J.69_Haemoflagellates_of_Sloths.pdf PDF]) *{{cite book | author = Myler and Fasel | title = Leishmania: After The Genome | publisher = Caister Academic Press | year = 2008 | url=http://www.horizonpress.com/leish | id = [http://www.horizonpress.com/leish ISBN 978-1-904455-28-8 ]}} ==References== <!-- --------------------------------------------------------------- See http://en.wikipedia.org/wiki/Wikipedia:Footnotes for a discussion of different citation methods and how to generate footnotes using the <ref> & </ref> tags and the {{Reflist}} template -------------------------------------------------------------------- --> {{Reflist|2}} ==External links== {{Commonscat}} * The International Leishmania Network [http://www.bdt.org.br/leishnet/ (ILN)] has basic information on the disease and links to many aspects of the disease and its vector. * A discussion list [http://www.bdt.fat.org.br/listas/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. * [http://www.kinetoplastids.com/ KBD: Kinetoplastid Biology and Disease], is a website devoted to leishmaniasis, sleeping sickness and [[Chagas]] (American trypanosomiasis). It contains free access to full length peer review articles on these subjects. The site contains many articles relating to the unique kinetoplastid organelle and genetic material therein. [[Category:Parasitic protists]] [[Category:Euglenozoa]] <!--[[ja:リーシュマニ��原虫]]--> [[ar:ليشمانيا]] [[ca:Leishmània]] [[de:Leishmanien]] [[es:Leishmania]] [[fr:Leishmania]] [[ka:ლეიშმანია]] [[ja:リーシュマニア]] [[pt:Leishmania]] [[ru:Лейшмании]] [[tr:Leishmania]]