| Leishmania | |
|---|---|
 | |
| L. donovani in bone marrow cell | |
Scientific classification | |
| Domain: | Eukaryota |
| Clade: | Discoba |
| Phylum: | Euglenozoa |
| Class: | Kinetoplastea |
| Order: | Trypanosomatida |
| Family: | Trypanosomatidae |
| Genus: | Leishmania Ross, 1903 |
| Species | |
L. aethiopica | |
Leishmania (/liːʃˈmeɪniə,-ˈmæn-/[1]) is a genus of parasiticprotozoans, single-celledeukaryotic organisms of thetrypanosomatid group that are responsible for the diseaseleishmaniasis.[2][3][4] The parasites are transmitted bysandflies of the genusPhlebotomus in theOld World, and of the genusLutzomyia in theNew World. There are 53 species and about 20 of them are responsible for human infections.[5][6] They are transmitted by around 100 species of sandflies.[7] The primary hosts arevertebrates. They commonly infecthyraxes,canids,rodents, andhumans.
Members of an ancientgenus ofLeishmania-like parasites,Paleoleishmania, have been detected infossilizedsand flies dating back to the earlyCretaceous period.[8] The first written reference to the conspicuous symptoms ofcutaneous leishmaniasis surfaced in thePaleotropics withinoriental texts dating back to the 7th century BC (allegedly transcribed from sources several hundred years older, between 1500 and 2000 BC[9]). 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.[10]
In India, both cutaneous andvisceral leishmaniasis are caused byLeishmania donovani.[11][12] 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";[13] while the visceral form was variously called "Burdwan [after the cityBurdwan] fever", "kala azar" (black fever), or "Dumdum [a city in West Bengal] fever".[14]
The causative parasite for the disease was identified in 1901 as a concurrent finding byWilliam Boog Leishman andCharles 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 astrypanosomatidprotozoans under thephylogenetic designation,Leishmania donovani. Several species have since been classified and grouped under two major subgenera i.e.Leishmania Viannia (generally located in theNeotropics) orLeishmania Leishmania (generally located in thePaleotropics, with the major exception of theL. mexicana subgroup).[15]
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 azoonosis.
Leishmania species areunicellular eukaryotes having a well-definednucleus and other cell organelles includingkinetoplasts andflagella. Depending on the stage of their life cycle, they exist in two structural variants, as:[16][17]
The details of the evolution of this genus are debated, butLeishmania apparently evolved from an ancestral trypanosome lineage. The oldest lineage is that of theBodonidae, followed byTrypanosoma brucei, the latter being confined to the African continent.Trypanosoma cruzi groups withtrypanosomes from bats, South American mammals, andkangaroos suggest an origin in the Southern Hemisphere. These clades are only distantly related.
The remaining clades in this tree areBlastocrithidia,Herpetomonas, andPhytomonas. The four generaLeptomonas,Crithidia,Leishmania, andEndotrypanum form the terminal branches, suggesting a relatively recent origin. Several of these genera may be polyphyletic and may need further division.[18]
The origins of genusLeishmania itself are unclear.[19][20] One theory proposes an African origin, with migration to the Americas. Another proposes migration from the Americas to theOld World via theBering Strait land bridge around 15 million years ago. A third theory proposes aPalearctic origin.[21] Such migrations would entail subsequent migration of vector and reservoir or successive adaptations along the way. A more recent migration is that ofL. infantum from Mediterranean countries toLatin America (known asL. chagasi), since European colonization of theNew World, where the parasites picked up their current New Worldvectors in their respective ecosystems.[22] This is the cause of the epidemics now evident. One recent New World epidemic concerns foxhounds in the USA.[23]
Although it was suggested thatLeishmania might have evolved in theNeotropics,[24] this is probably true for species belonging to the subgeneraViannia andEndotrypanum. However, there is evidence that the primary evolution of the subgeneraLeishmania andSauroleishmania is the Old World. While theMundinia 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 thatLeishmania evolved 90 to 100 million years ago inGondwana.[25] The reptile infecting species originated in mammalian clades.
Sauroleishmania species were originally defined on the basis that they infectedreptiles (lizards) rather thanmammals. Based on molecular evidences, they have been moved to subgenus status withinLeishmania. This subgenus probably evolved from a group that originally infected mammals.[26]
53 species are recognised in this genus. The status of several of these is disputed, so the final number may differ.[6] At least 20 species infect humans.[7] To make things more complex,hybrids might be involved, as it has been reported in Brazil with a hybrid betweenLeishmania (V.) guyanensis andLeishmania (V.) shawi shawi.[27]
The genus is presently divided into 4 subgenera:Leishmania,Sauroleishmania,Mundinia andViannia. The division into the two subgenera (Leishmania andViannia) was made by Lainson and Shaw in 1987 on the basis of their location within the insect gut. The species in theViannia 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 subgenusMundinia while revising Leishmaniinae in 2016.[28]
Endotrypanum is closely related toLeishmania. SomeEndotypanum species are unique in that they infect the erythrocytes of their hosts (sloths). All species are confined to Central and South America.[29]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 theLeishmania intoEuleishmania andParaleishmania groups in 2000 emphasized the deep phylogenic distance between parasites, some of which had been named asLeishmania species.[30] TheEuleishmania included species currently placed in the subgeneraLeishmania,Sauroleishmania,Mundinia andViannia. The proposedParaleishmania included species ofEndotypanum,Leishmamnia-L. colomubensis,L. herreri,L. hertigiandL. deanei andL. equatorensis. In a recent revision these species were given different generic status.
Four subgenera ofLeishmania are now recognised -Leishmania,Sauroleishmania,Viannia andMundinia (theL. enriettii complex). The genusEndotrypanum andPorcisia belong to theParaleishmania.
There are fourMundinia species -L. (Mundinia) enriettii,L. (Mundinia) martiniquensis,L. (Mundinia) macropodum, andL. (Mundinia) orientalis, which is found in Thailand.[31]
L. archibaldi's specific status is unsettled but it is closely related toL. donovani.
L. herreri belongs to the genusEndotypanum rather than toLeishmania.
L. donovani andL. infantum are closely related.
The selenoenzymeSeltryp appears to be unique to this order.[32] It has been removed from the subgenusViannia.
L. deanei andL. hertigi, both of which infect porcupines have been moved to the genusPorcisia.
SubgenusLeishmaniaRoss, 1903 sensu Saf'janova, 1982
SubgenusMundiniaShaw,Camargo and Teixeira 2016
SubgenusSauroleishmaniaRanque, 1973 sensu Saf'janova, 1982
↑ Species described asSauroleishmania. Their development is not like other members of the subgenus and so their taxonomic position is doubtful.
SubgenusVianniaLainson & Shaw 1987
The relationships betweenLeishmania and other genera such asEndotrypanum,Novymonas,Porcisia, andZelonia is presently unclear as they are closely related.[34][15]Endotrypanum colombiensis, formerly known asLeishmania colombiensis, has been associated with both cutaneous and visceral leishmaniasis in Venezuela.[35]
GenusEndotrypanum
GenusNovymonasKostygov and Yurchenko 2016
GenusPorcisiaShaw, Camargo and Teixeira, 2016
GenusZeloniaShaw, Camargo and Teixeira, 2016
The biochemistry and cell biology ofLeishmania is similar to that of otherkinetoplastids. They share the same main morphological features: a singleflagellum which has an invagination - the flagellar pocket - at its base; akinetoplast, which is found in the singlemitochondrion; and a subpelicular array of microtubules, which make up the main part of thecytoskeleton.
Leishmania possesses alipophosphoglycan coat over the outside of the cell. Lipophosphoglycan is a trigger fortoll-like receptor 2, a signalling receptor involved in triggering aninnate immune response in mammals.
The precise structure of lipophosphoglycan varies depending on the species andlifecycle stage of the parasite. The glycan component is particularly variable and different lipophosphoglycan variants can be used as amolecular marker for different lifecycle stages.Lectins, a group ofproteins 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 ofL. 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 theLeishmania parasites live withinmacrophages and need to prevent the macrophages from killing them. Lipophosphoglycan has a role in resisting thecomplement system, inhibiting theoxidative burst response, inducing aninflammation response and preventingnatural killer T cells recognising that the macrophage is infected with theLeishmania parasite.
| Type | Pathogen | Location |
|---|---|---|
| Cutaneous leishmaniasis (localised and diffuse) infections appear as obvious skin reactions. | The most common is theOriental Sore (caused by Old World speciesL. major,L. tropica, andL. aethiopica). In the New World, the most common culprits isL. mexicana. | Cutaneous infections are most common inAfghanistan,Brazil,Iran,Peru,Saudi Arabia andSyria. |
| Mucocutaneous leishmaniasis infections start off as a reaction at the bite, and can go bymetastasis into the mucous membrane and become fatal. | L. braziliensis | Mucocutaneous infections are most common inBolivia,Brazil andPeru. Mucocutaneous infections are also found inKaramay, China Xinjiang Uygur Autonomous Region. |
| Visceral leishmaniasis infections are often recognised by fever, swelling of the liver and spleen, andanemia. They are known by many local names, of which the most common is probablykala azar,[36][37] | Caused exclusively by species of theL. donovani complex (L. donovani,L. infantum syn.L. chagasi).[2] | Found in tropical and subtropical areas of all continents exceptAustralia, visceral infections are most common inBangladesh,Brazil,India,Nepal, andSudan.[2] Visceral leishmaniasis also found in part of China, such as Sichuan Province, Gansu Province, and Xinjiang Uygur Autonomous Region. |
In order to avoid destruction by theimmune system and thrive, theLeishmania 'hides' inside its host's cells. This location enables it to avoid the action of thehumoral 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 discourageapoptosis. The primary cell typesLeishmania infiltrates arephagocytotic cells such asneutrophils andmacrophages.[38]
Usually, a phagocytotic immune cell like a macrophage will ingest a pathogen within an enclosedendosome and then fill this endosome with enzymes which digest the pathogen. However, in the case ofLeishmania, 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.[39]
Transmitted by thesandfly, theprotozoanparasites ofL. major may switch the strategy of the first immune defense from eating/inflammation/killing to eating/no inflammation/no killing of their hostphagocyte and corrupt it for their own benefit.[citation needed] They use the willingly phagocytosing polymorphonuclear neutrophil granulocytes (PMNs) rigorously as a tricky hideout, where theyproliferate unrecognized from the immune system and enter the long-livedmacrophages to establish a "hidden"infection.[citation needed]
Uponmicrobial 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 secretechemokines,IL-8 particularly, to attract furthergranulocytes and stimulate phagocytosis. Further,L. major increases the secretion of IL-8 by PMNs. This mechanism is observed during infection with otherobligate 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 signalphosphatidylserine usually found on apoptotic cells, is exposed on the surface of dead parasites,L. major switches off theoxidative burst, thereby preventing killing and degradation of the viable pathogen.
In the case ofLeishmania, 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 releaseLeishmania chemotactic factor (LCF) to actively recruit neutrophils, but not otherleukocytes, for instancemonocytes orNK cells. In addition to that, the production ofinterferon gamma (IFNγ)-inducible protein 10 (IP10) by PMNs is blocked in attendance ofLeishmania, what involves the shut down of inflammatory and protective immune response by NK andTh1 cell recruitment. The pathogens stay viable during phagocytosis since their primary hosts, the PMNs, expose apoptotic cell-associated molecular pattern (ACAMP) signaling "no pathogen".
The lifespan ofneutrophil granulocytes is quite short. They circulate inbloodstream for about 6 to 10 hours after leavingbone marrow, whereupon they undergo spontaneousapoptosis. Microbial pathogens have been reported to influence cellular apoptosis by different strategies. Obviously because of the inhibition ofcaspase3-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.[40]
An important factor in prolonging infection is the inhibition ofthe 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 ofphagocytes are targeted.[41] For example,mincle has been shown to be targeted byL. major. Interaction between mincle and a protein released by the parasite results in a weakened immune response indendritic cells.[42]
To save the integrity of the surrounding tissue from thetoxic cell components andproteolyticenzymes contained in neutrophils, the apoptotic PMNs are silently cleared by macrophages. Dying PMNs expose the "eat me"-signalphosphatidylserine which is transferred to the outer leaflet of theplasma membrane during apoptosis. By reason of delayed apoptosis, the parasites that persist in PMNs are taken up into macrophages, employing an absolutelyphysiological and nonphlogistic process. The strategy of this "silent phagocytosis" has the following advantages for the parasite:
However, studies have shown this is unlikely, as the pathogens are seen to leave apoptotic cells and no evidence is known of macrophage uptake by this method.
An important aspect of theLeishmania protozoan is itsglycoconjugate layer oflipophosphoglycan (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 anendosome fusing with alysosome, releasing acidhydrolases which degradeDNA,RNA, proteins andcarbohydrates.
The genomes of fourLeishmania species (L. major,L. infantum,L. donovani andL. braziliensis) have been sequenced, revealing more than 8300 protein-coding and 900RNA 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 differentloci throughout thegenome. Each of the 35 or 36chromosomes 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 bytRNA,rRNA and/orsnRNA genes. Transcription of protein-coding genes initiates bidirectionally in the divergent strand-switch regions between gene clusters and extends polycistronically through each gene cluster before terminating in the strand-switch region separating convergent clusters.Leishmaniatelomeres 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. TheL. major andL. infantum genomes contain only about 50 copies of inactive degeneratedIngi/L1Tc-related elements (DIREs), whileL. braziliensis also contains several telomere-associated transposable elements and spliced leader-associated retroelements. TheLeishmania genomes share a conserved core proteome of about 6200 genes with the related trypanosomatidsTrypanosoma brucei andTrypanosoma cruzi, but around 1000Leishmania-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 sequencedLeishmania 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.[3]
Leishmania species produce several differentheat shock proteins. These include Hsp83, a homolog ofHsp90. A regulatory element in the3' UTR of Hsp83 controlstranslation of Hsp83 in a temperature-sensitive manner. This region forms a stableRNA structure which melts at higher temperatures.[43]
Leishmania lacks of promoter-dependent regulation, so its genomic regulation is at post-transcriptional level throughcopy 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 involvesepistatic interactions between genes, which drive these changes in gene expression, leading to compensatory mechanisms in theLeishmania 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 (GWAS) ofLeishmania donovani identified CNVs in 14% of the coding regions and in 4% of the non-coding regions. In addition, anexperimental 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, aNIMA-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 toflagellar 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) andnucleolar 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 ismethylation and inclusion ofpseudouridine 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 ofLeishmania 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.[44]
A microbial pathogen's reproductive system is one of the basic biologic processes that condition the microorganism's ecology and disease spread.[45] In 2009 Akopyants et al.[46] demonstrated thatL. 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 thesand fly vector, and hybrids can be transmitted to the mammalian host by sand fly bite. InL. braziliensis matings in nature are predominantly between related individuals resulting in extreme inbreeding.[47] The rate of outcrossing between different strains ofLeishmania in the sand fly vector depends on the frequency of co-infection. Such outcrossing events appear to be rare inL. major[46] andL. donovani.[48]
L. infantum produces proteins BRCA1 and RAD51 that interact with each other to promote homologous recombinational repair.[49] 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[50]
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