Leishmania

Source: Wikipedia, the free encyclopedia.
This article is about the parasite. For the infection, see Leishmaniasis.

Leishmania
L. donovani in bone marrow cell
Scientific classification Edit this classification
Domain: Eukaryota
Phylum: Euglenozoa
Class: Kinetoplastea
Order: Trypanosomatida
Genus: Leishmania
Ross, 1903
Species

L. aethiopica
L. amazonensis
L. arabica
L. archibaldi (starus species)
L. aristedesi (status disputed)
L. (Viannia) braziliensis

L. chagasi
(syn. L. infantum)
L. donovani
L. (Mundinia) enriettii
L. forattinii (status disputed)
L. garnhami (status disputed)
L. gerbili
L. (Viannia) guyanensis
L. infantum
L. killicki (status disputed)
L. (Viannia) lainsoni
L. major
L. (Mundinia) macropodum
L. (Mundinia) martiniquensis
L. mexicana
L. (Viannia) naiffi
L. (Viannia) panamensis
L. (Viannia) peruviana
L. pifanoi (status disputed)
L. (Viannia) shawi
L. tarentolae
L. tropica
L. turanica
L. waltoni
L. venezuelensis

Leishmania

canids, rodents, and humans
.

History

Members of an ancient

black fever". Some of these names suggest links to negative cultural beliefs or mythology, which still feed into the social stigmatization of leishmaniasis today.[8]

In India, both cutaneous and

Burdwan] fever", "kala azar" (black fever), or "Dumdum [a city in West Bengal] fever".[12]

The causative parasite for the disease was identified in 1901 as a concurrent finding by

Paleotropics, with the major exception of the L. mexicana subgroup).[13]

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

flagella. Depending on the stage of their life cycle, they exist in two structural variants, as:[14][15]

  1. 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 µm in length and 1–3 µm in breadth. The kinetoplast and basal body lie towards the anterior end.
  2. 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 µm in length and 5 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.
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 trypanosomes from bats, South American mammals, and kangaroos 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.[16]

The origins of genus Leishmania itself are unclear.

vectors in their respective ecosystems.[20] This is the cause of the epidemics now evident. One recent New World epidemic concerns foxhounds in the USA.[21]

Although it was suggested that Leishmania might have evolved in the

Neotropics,[22]
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.[23] The reptile infecting species originated in mammalian clades.

Sauroleishmania species were originally defined on the basis that they infected reptiles (lizards) rather than mammals. Based on molecular evidences, they have been moved to subgenus status within Leishmania. This subgenus probably evolved from a group that originally infected mammals.[24]

Taxonomy

53 species are recognised in this genus. The status of several of these is disputed, so the final number may differ. At least 20 species infect humans. To make things more complex, hybrids might be involved, as it has been reported in Brazil with a hybrid between Leishmania (V.) guyanensis and Leishmania (V.) shawi shawi.[25]

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.[26]

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.[27] 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.[28] 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. hertigiand 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.[29]

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.[30] 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 Ross, 1903 sensu Saf'janova, 1982

Subgenus Mundinia Shaw,Camargo and Teixeira 2016

Subgenus Sauroleishmania Ranque, 1973 sensu Saf'janova, 1982

↑ Species described as Sauroleishmania. Their development is not like other members of the subgenus and so their taxonomic position is doubtful.

Subgenus Viannia Lainson & Shaw 1987

Related genera

The relationships between Leishmania and other genera such as Endotrypanum, Novymonas, Porcisia, and Zelonia is presently unclear as they are closely related.[32][13] Endotrypanum colombiensis, ofter known as Leishmania colombiensis, has been associated with both cutaneous and visceral leishmaniasis in Venezuela.[33]

Genus Endotrypanum

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

Genus Novymonas Kostygov and Yurchenko 2016

  • Novymonas esmeraldas Votýpka, Kostygov, Maslov and Lukeš, 2016

Genus Porcisia Shaw, Camargo and Teixeira, 2016

  • Porcisia deanei Lainson & Shaw, 1977
  • Porcisia hertigi Herrer, 1971

Genus Zelonia Shaw, Camargo and Teixeira, 2016

  • Zelonia australiensis Barratt, Kaufer, Peters, Craig, Lawrence, Roberts, Lee, McAuliffe, Stark, Ellis, 2017
  • Zelonia costaricensis Yurchenko, Lukes, Jirku, Zeledon, Maslov, 2006

Biochemistry and cell biology

The biochemistry and cell biology of Leishmania is similar to that of other 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

toll-like receptor 2, a signalling receptor involved in triggering an innate immune response
in mammals.

The precise structure of lipophosphoglycan varies depending on the species and

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

natural killer T cells
recognising that the macrophage is infected with the Leishmania parasite.

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 L. major, L. tropica, and L. aethiopica). In the New World, the most common culprits is L. mexicana. Cutaneous infections are most common in Afghanistan, Brazil, Iran, Peru, Saudi Arabia and Syria.
Mucocutaneous leishmaniasis infections start off as a reaction at the bite, and can go by metastasis
into the mucous membrane and become fatal. 		L. braziliensis Mucocutaneous infections are most common in Bolivia, Brazil and Peru. Mucocutaneous infections are also found in Karamay, China Xinjiang Uygur Autonomous Region.
kala azar,[34][35]
 Caused exclusively by species of the L. donovani complex (L. donovani, L. infantum syn. L. chagasi).[2] Found in tropical and subtropical areas of all continents except Australia, visceral infections are most common in Bangladesh, Brazil, India, Nepal, and Sudan.[2] 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

macrophages.[36]

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.[37]

Transmitted by the

macrophages to establish a "hidden" infection.[citation needed
]

Uptake and survival

Lifecycle of Leishmania

Upon

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

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

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 caspase3-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.[38]

An important factor in prolonging infection is the inhibition of 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 phagocytes are targeted.[39] For example, 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 cells.[40]

Silent phagocytosis theory

To save the integrity of the surrounding tissue from the

plasma membrane during apoptosis. By reason of delayed apoptosis, the parasites that persist in PMNs are taken up into macrophages, employing an absolutely physiological
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 apoptopic cells and no evidence is known of macrophage uptake by this method.

Molecular biology

An important aspect of the Leishmania protozoan is its

carbohydrates
.

Genomics

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

snRNA 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. Leishmania telomeres 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.[3]

Leishmania species produce several different

translation of Hsp83 in a temperature-sensitive manner. This region forms a stable RNA structure which melts at higher temperatures.[41]

Genomic instability

Leishmania lacks of promoter-dependent regulation, so its genomic regulation is at post-transcriptional level through 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 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 (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 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 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 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,

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 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. [42]

Sexual reproduction

A microbial pathogen's reproductive system is one of the basic biologic processes that condition the microorganism's ecology and disease spread.

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.[45] 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 [44] and L. donovani.[46]

L. infantum produces proteins BRCA1 and RAD51 that interact with each other to promote homologous recombinational repair.[47] 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[48]

See also

References

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Further reading

External links

Wikimedia Commons has media related to Leishmania.
  • A discussion list (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.
  • 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.
  • Drug Search for Leishmaniasis World Community Grid