Leishmania major

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Leishmania major
Leishmania major promastigotes.jpg
Promastigotes of Leishmania major, 10×100, Giemsa stain.
Scientific classification OOjs UI icon edit-ltr.svg
Domain: Eukaryota
Phylum: Euglenozoa
Class: Kinetoplastea
Order: Trypanosomatida
Genus: Leishmania
Species:
L. major
Binomial name
Leishmania major
Yakimoff and Schokhor, 1914

Leishmania major is a species of parasite found in the genus Leishmania , and is associated with the disease zoonotic cutaneous leishmaniasis (also known as Aleppo boil, Baghdad boil, Bay sore, Biskra button, Chiclero ulcer, Delhi boil, Kandahar sore, Lahore sore, Oriental sore, Pian bois, and Uta). [1] L. major is an intracellular pathogen which infects the macrophages and dendritic cells of the immune system. [2] Though Leishmania species are found on every continent aside from Antarctica, Leishmania major is found only in the Eastern Hemisphere, specifically in Northern Africa, [3] the Middle East, Northwestern China, and Northwestern India. [4] [5]

Contents

Biology

Life cycle

As a trypanosomatid, L. major begins its lifecycle in amastigote form in the midgut of the main vector, female sand flies ( Phlebotomus spp. ). [6] Once in the gut of the sand fly, the parasites change from aflagelated amastigotes into

Leishmania major Life Cycle Leishmaniasis life cycle diagram en.svg
Leishmania major Life Cycle

flagellated promastigotes for 1–2 weeks until they are fully developed, a which point they make their way to the proboscis. [5] Upon biting a mammalian host, promastigotes are released into the bloodstream, where they are engulfed by macrophages. [7] Following engulfment, promastigotes differentiate into amastigotes. [7] Amastigotes are oval or round, and have a diameter between 2-3μm. [5] Additionally, they contain a large, eccentrically placed nucleus along with a kinetoplast (which holds extracellular DNA). [5] Being equipped to survive the acidic environment inside the phagosomes of macrophages, the amastigotes reproduce through the process of binary fission. [5] At this point the amastigotes are released throughout the body, and can be ingested by female sand flies, thus completing the cycle. [7] L. major has a sexual cycle, including a meiotic process. [8] Mating only occurs in the sand fly vector. [9]

Hosts

Meriones unguiculatus , other Meriones and jirds, and other rodents are common hosts. Dogs, [10] [11] : 2  Mustela nivalis , [10] Atelerix algirus , [10] and Paraechinus aethiopicus [10] are rare hosts. Mice are natural hosts. [12] Transmission between mice is via Phlebotomus papatasi . [12]

Infection

Upon entering the mammalian bloodstream, L. major meets the focal point of infection, the macrophage. As a result of two surface molecules, the protease gp63 and a lipophosphoglycan, promastigotes are able to bind to several macrophage receptors. [13] [14] Promastigote attachment to macrophages is facilitated by a number of receptors, including complement receptors CR1 and CR3, and the receptor for advanced glycosylation end products. [5] Activation of complements occurs far from the cell membrane, and insertion of the membrane attack complex does not occur. [5] This action is what allows the parasite to avoid being lysed, and to persist within the host's macrophages. In cattle Th1 and Th2 cells are an important part of the response. [15] Neither cell type expresses exclusively IFNγ or IL-4 for L. major – Brown et al. 1998 find they express both in cattle. [15] The bovine myeloid antimicrobial peptide BMAP-28 has leishmanicidal activity and may be usable in vivo in cattle infection. [16] Lynn et al., 2011 obtain good results against two strains of the parasite, using two isoforms of BMAP-28, the retro-inverso and the D-amino acid. [16]

Enzymatics

Dimethylallyltranstransferase is vital to L. major, making it an interesting target for leishmaniacidal substances. [17] Propenko et al. 2014 present and validate several dimethylallyltranstransferase inhibitors. [17]

Epidemiology

Cutaneous leishmaniasis in North Africa; Leishmania major infected areas are in blue Parasite130072-fig1 Map of cutaneous leishmaniasis in North Africa.tif
Cutaneous leishmaniasis in North Africa; Leishmania major infected areas are in blue

The incidence rate of cutaneous leishmaniasis is estimated to be between 1–1.5 million cases a year. [18] However, transmission does not often occur in utero , during blood transfusions, or through interpersonal contact. [5] Thus, the main form of transmission is through the sand fly vector. Sand flies do not fly long distances, and tend to complete their life cycles in areas with a diameter of less than 1 km. [7] Furthermore, because of the propensity of sand flies to seek out shelter in the burrows of small rodents, [7] where L. major is endemic, small mammals such as gerbils and birds serve as the main reservoirs. [5] Dogs have also been documented as contracting cutaneous leishmaniasis in Egypt [19] and Saudi Arabia. [20] This is rare however, and dogs are not important hosts for L. major.

L. major and its cousin, L. tropica , are recognized as causing the majority of cases of cutaneous leishmaniasis across the Middle East, Northern Africa, and some areas of China and India (as mentioned above). Between 2002 and 2004, over 700 cases of the disease were reported among United States military personnel serving in Iraq. [21]

Clinical manifestations

Cutaneous Leishmaniasis Sore Leishmaniose cutanee - Guyane fr.JPG
Cutaneous Leishmaniasis Sore

Upon becoming infected, patients usually present with lesions at the site of the sand fly bite. The infection is acute, and usually has a duration of about 3–6 months. [4] As more and more phagocytic cells engulf promastigotes, prompting the production of amastigotes, nodules form on the skin. [5] These nodules then ulcerate, although due to the variable characteristics of the lesions, species specific identification of the pathogen is impossible. [5] Generally though, lesions appear moist and have raised outer borders, a granulating base, an overlying layer of white purulent exudate, and have been described as "pizza-like." [4] [5] Biopsies of these lesions usually reveal a number of findings including numerous macrophages containing intracellular amastigotes as well as lymphocytes with observed granuloma formation and few parasites. [22]

Diagnosis

Leishmania major should be considered in the differential diagnosis of chronic lesions of people who have spent time in areas where it is endemic. However, other pathogens can cause similar lesions and therefore paracoccidiodomycosis, histoplasmosis, sporotrichosis, lobomycosis, lupus vulgaris, Mycobacterium ulcerans , syphilis, cutaneous sarcoidosis, and leprosy should all be considered as well. [5]

The most common ways of diagnosing leishmaniasis are to identify amastigotes in a Wright-Giemsa-stained touch preparation or through isolation of the parasites in cultures. [5]

Treatment

Because the host's immune system tends to resolve infection after 3–6 months, treatment of the lesions generally focuses on limiting tissue damage and necrosis. [4] [5] A number of different treatments have yielded results of varying effectiveness in the treatment of L. major caused cutaneous leishmaniasis.

Prevention

The spread of leishmaniasis can be prevented by interrupting the sand fly life cycle or removing or treating pathogen reservoirs. Avoiding sand fly bites is an effective means of avoiding disease for short term visitors to areas where L. major is endemic. This can be accomplished through the use of DEET containing insect repellent, application of insecticides to clothes and bedding, as well as using mosquito nets to cover beds. [5] Sand flies usually bite between dusk and dawn, so preventative measures should be taken during these times. [7]

Though a vaccine does not yet exist that can prevent cutaneous leishmaniasis, it is speculated that one will be developed in the near future. [5] Patients who have recovered from L. major infections develop high- level immunity to the pathogen. [5] In Russia and Israel, soldiers were "immunized" against L. major through the injection of live promastigotes into the buttocks; however, this form of treatment was discontinued in Israel due to the occasional formation of large or slow-healing lesions. [5]

Related Research Articles

<i>Leishmania</i> Genus of parasitic flagellate protist

Leishmania is a parasitic protozoan, a single-celled organism of the genus Leishmania that is responsible for the disease leishmaniasis. They are spread by sandflies of the genus Phlebotomus in the Old World, and of the genus Lutzomyia in the New World. At least 93 sandfly species are proven or probable vectors worldwide. Their primary hosts are vertebrates; Leishmania commonly infects hyraxes, canids, rodents, and humans.

<span class="mw-page-title-main">Trypanosomatida</span> Flagellate kinetoplastid excavate order

Trypanosomatida is a group of kinetoplastid unicellular organisms distinguished by having only a single flagellum. The name is derived from the Greek trypano (borer) and soma (body) because of the corkscrew-like motion of some trypanosomatid species. All members are exclusively parasitic, found primarily in insects. A few genera have life-cycles involving a secondary host, which may be a vertebrate, invertebrate or plant. These include several species that cause major diseases in humans. Some trypanosomatida are intracellular parasites, with the important exception of Trypanosoma brucei.

<span class="mw-page-title-main">Leishmaniasis</span> Disease caused by parasites of the Leishmania type

Leishmaniasis is a wide array of clinical manifestations caused by protozoal parasites of the Trypanosomatida genus Leishmania. It is generally spread through the bite of phlebotomine sandflies, Phlebotomus and Lutzomyia, and occurs most frequently in the tropics and sub-tropics of Africa, Asia, the Americas, and southern Europe. The disease can present in three main ways: cutaneous, mucocutaneous, or visceral. The cutaneous form presents with skin ulcers, while the mucocutaneous form presents with ulcers of the skin, mouth, and nose. The visceral form starts with skin ulcers and later presents with fever, low red blood cell count, and enlarged spleen and liver.

<span class="mw-page-title-main">Sandfly</span> Name of several types of blood-sucking fly

Sandfly or sand fly is a colloquial name for any species or genus of flying, biting, blood-sucking dipteran (fly) encountered in sandy areas. In the United States, sandfly may refer to certain horse flies that are also known as "greenheads", or to members of the family Ceratopogonidae. The bites usually result in a small, intensely itchy bump or welt, the strength of which intensifies over a period of 5-7 days before dissipating. Moderate relief is achieved with varying success through the application of over the counter products such as Benadryl (ingested) or an analgesic cream such as After Bite. Outside the United States, sandfly may refer to members of the subfamily Phlebotominae within the Psychodidae. Biting midges (Ceratopogonidae) are sometimes called sandflies or no-see-ums. New Zealand sandflies are in the genus of sand fly Austrosimulium, a type of black fly.

<i>Lutzomyia</i> Genus of flies

Lutzomyia is a genus of phlebotomine sand flies consisting of nearly 400 species, at least 33 of which have medical importance as vectors of human disease. Species of the genus Lutzomyia are found only in the New World, distributed in southern areas of the Nearctic and throughout the Neotropical realm. Lutzomyia is one of the two genera of the subfamily Phlebotominae to transmit the Leishmania parasite, with the other being Phlebotomus, found only in the Old World. Lutzomyia sand flies also serve as vectors for the bacterial Carrion's disease and a number of arboviruses.

<i>Phlebotomus</i> Genus of flies

Phlebotomus is a genus of "sand flies" in the Diptera family Psychodidae. In the past, they have sometimes been considered to belong in a separate family, Phlebotomidae, but this alternative classification has not gained wide acceptance.

<span class="mw-page-title-main">Cutaneous leishmaniasis</span> Medical condition

Cutaneous leishmaniasis is the most common form of leishmaniasis affecting humans. It is a skin infection caused by a single-celled parasite that is transmitted by the bite of a phlebotomine sand fly. There are about thirty species of Leishmania that may cause cutaneous leishmaniasis.

<span class="mw-page-title-main">Visceral leishmaniasis</span> Human disease caused by protist parasites

Visceral leishmaniasis (VL), also known as kala-azar or "black fever", is the most severe form of leishmaniasis and, without proper diagnosis and treatment, is associated with high fatality. Leishmaniasis is a disease caused by protozoan parasites of the genus Leishmania.

<span class="mw-page-title-main">Miltefosine</span> Phospholipid drug

Miltefosine, sold under the trade name Impavido among others, is a medication mainly used to treat leishmaniasis and free-living amoeba infections such as Naegleria fowleri and Balamuthia mandrillaris. This includes the three forms of leishmaniasis: cutaneous, visceral and mucosal. It may be used with liposomal amphotericin B or paromomycin. It is taken by mouth.

<span class="mw-page-title-main">Disease vector</span> Agent that carries and transmits an infectious pathogen into another living organism

In epidemiology, a disease vector is any living agent that carries and transmits an infectious pathogen such as a parasite or microbe, to another living organism. Agents regarded as vectors are mostly blood-sucking insects such as mosquitoes. The first major discovery of a disease vector came from Ronald Ross in 1897, who discovered the malaria pathogen when he dissected the stomach tissue of a mosquito.

<span class="mw-page-title-main">Protozoan infection</span> Parasitic disease caused by a protozoan

Protozoan infections are parasitic diseases caused by organisms formerly classified in the kingdom Protozoa. These organisms are now classified in the supergroups Excavata, Amoebozoa, Harosa, and Archaeplastida. They are usually contracted by either an insect vector or by contact with an infected substance or surface.

<span class="mw-page-title-main">Canine leishmaniasis</span> Disease affecting dogs

Canine leishmaniasis (LEESH-ma-NIGH-ah-sis) is a zoonotic disease caused by Leishmania parasites transmitted by the bite of an infected phlebotomine sandfly. There have been no documented cases of leishmaniasis transmission from dogs to humans. Canine leishmaniasis was first identified in Europe in 1903, and in 1940, 40% of all dogs in Rome were determined to be positive for leishmaniasis. Traditionally thought of as a disease only found near the Mediterranean basin, 2008 research claims new findings are evidence that canine leishmaniasis is currently expanding in continental climate areas of northwestern Italy, far from the recognized disease-endemic areas along the Mediterranean coasts. Cases of leishmaniasis began appearing in North America in 2000, and, as of 2008, Leishmania-positive foxhounds have been reported in 22 U.S. states and two Canadian provinces.

<i>Leishmania donovani</i> Species of intracellular parasite

Leishmania donovani is a species of intracellular parasites belonging to the genus Leishmania, a group of haemoflagellate kinetoplastids that cause the disease leishmaniasis. It is a human blood parasite responsible for visceral leishmaniasis or kala-azar, the most severe form of leishmaniasis. It infects the mononuclear phagocyte system including spleen, liver and bone marrow. Infection is transmitted by species of sandfly belonging to the genus Phlebotomus in Old World and Lutzomyia in New World. The species complex it represents is prevalent throughout tropical and temperate regions including Africa, China, India, Nepal, southern Europe, Russia and South America. The species complex is responsible for thousands of deaths every year and has spread to 88 countries, with 350 million people at constant risk of infection and 0.5 million new cases in a year.

<i>Leishmania tropica</i> Species of protozoan parasite

Leishmania tropica is a flagellate parasite and the cause of anthroponotic cutaneous leishmaniasis in humans. This parasite is restricted to Afro-Eurasia and is a common cause of infection in Afghanistan, Iran, Syria, Yemen, Algeria, Morocco, and northern India.

Leishmania braziliensis is a Leishmania species found in South America. It is associated with leishmaniasis.

<i>Leishmania mexicana</i> Species of parasitic protist

Leishmania mexicana is a species of obligate intracellular parasites of the protozoan genus Leishmania. In Mexico and Central America, this parasite is the primary cause of cutaneous leishmaniasis.

<i>Paleoleishmania</i> Extinct genus of parasitic flagellate protist in the Kinetoplastea class

Paleoleishmania is an extinct genus of kinetoplastids, a monophyletic group of unicellular parasitic flagellate protozoa. At present it is placed in the family Trypanosomatidae. The genus contains two species, the type species Paleoleishmania proterus and the later described Paleoleishmania neotropicum.

<i>Lutzomyia longipalpis</i> Species of fly

Lutzomyia longipalpis is a species complex of sandfly belonging to the family Psychodidae. This species is primarily present in Central and South America, but has also appeared in Mexico. There have been reports of L. longipalpis as far south as Argentina, as they are found in a wide variety of ecological conditions. Both males and females feed on sugars from plants and aphids, but only adult females feed on the blood of other mammals. The species has recently begun appearing in urban areas throughout Brazil, and serves as a key vessel for the propagation of the parasite Leishmania infantum. The presence of these flies appears to be strongly correlated to the presence of domestic chickens in Latin America. The first major urban outbreak of the lethal Visceral leishmanias epidemic was detected in Teresina, Piauí State in the early 1980s following a massive planting of acacias.

María Dora Feliciangeli was Professor of Medical Entomology at the University of Carabobo, Venezuela, who worked on the transmission of tropical parasites especially American trypanosomiasis and leishmaniasis. She was Coordinator of the National Reference Center of Sandflies and the Medical Entomology Section.

<i>Phlebotomus papatasi</i> Species of fly

Phlebotomus papatasi is a species of insects commonly known as sandflies. Due to their ectothermic climate limitations, P. papatasi are confined to regions with temperatures above sixty degrees Fahrenheit for at least three months of the year, spanning over much of the European Mediterranean, North Africa, the Middle East, and Central Asia. Around one thousand sandfly species have been described, belonging to the subfamily Phlebotominae within the family Psychodidae. The Psychodidae family belongs to the order Diptera within the class Insecta of the subphylum Hexapoda of the Arthropod phylum.

References

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  9. ↑ Inbar E, Akopyants NS, Charmoy M, Romano A, Lawyer P, Elnaiem DE, Kauffmann F, Barhoumi M, Grigg M, Owens K, Fay M, Dobson DE, Shaik J, Beverley SM, Sacks D (2013). "The mating competence of geographically diverse Leishmania major strains in their natural and unnatural sand fly vectors". PLOS Genet. 9 (7): e1003672. doi: 10.1371/journal.pgen.1003672 . PMC   3723561 . PMID   23935521.
  10. 1 2 3 4 Iowa State University; Institute for Cooperation in Animal Biologics; Iowa State University College of Veterinary Medicine; OIE Collaborating Centre for Diagnosis of Animal Disease and Vaccine Evaluation in the Americas; OIE Collaborating Centre for Day-One Veterinary Competencies and Continuing Education; United States Department of Agriculture (August 2017). "Leishmaniasis" (PDF).
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  13. ↑ Etges, R; Bouvier J; Bordier C (1986). "The major surface protein of Leishmania promastigotes is a protease". J Biol Chem. 261 (20): 9098–9101. doi: 10.1016/s0021-9258(18)67621-5 . PMID   3522584. S2CID   38584080.
  14. ↑ King, DL; Chang Y-D; Turco SJ (1987). "Cell surface lipophosphoglycan of Leishmania donovani". Molecular and Biochemical Parasitology. 24 (1): 47–53. doi:10.1016/0166-6851(87)90114-9. PMID   3614272.
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  17. 1 2 Vermelho, Alane B.; Capaci, Giseli R.; Rodrigues, Igor A.; Cardoso, Verônica S.; Mazotto, Ana Maria; Supuran, Claudiu T. (2017). "Carbonic anhydrases from Trypanosoma and 'Leishmania as anti-protozoan drug targets". Bioorganic & Medicinal Chemistry . 25 (5). Elsevier: 1543–1555. doi:10.1016/j.bmc.2017.01.034. ISSN   0968-0896. PMID   28161253.
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  22. ↑ Ridley, DS (1979). "The pathogenesis of cutaneous leishmaniasis". Transactions of the Royal Society of Tropical Medicine and Hygiene. 73 (2): 150–160. doi:10.1016/0035-9203(79)90199-8. PMID   473304.
  23. ↑ Alrajhi, AA; Ibrahim EA; De Vol EB; et al. (2002). "Fluconazole for the treatment of cutaneous leishamaniasis caused by Leishmania major". The New England Journal of Medicine. 346 (12): 891–895. doi: 10.1056/nejmoa011882 . PMID   11907288.
  24. ↑ el-On J, Halevy S, Grunwald MH, Weinrauch L (1992). "Topical treatment of Old World cutaneous leishmaniasis caused by Leishmania major: a double-blind control study". J Am Acad Dermatol. 27 (2 Pt 1): 227–231. doi:10.1016/0190-9622(92)70175-f. PMID   1430361.

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