Leishmania major

As a trypanosomatid, L. major begins its lifecycle in amastigote form in the midgut of the main vector, female sand flies (Phlebotomus {{abbr|spp.|species}}).{{cite web|title=Parasites - Leishmaniasis|url=https://www.cdc.gov/parasites/leishmaniasis/biology.html|publisher=Centers for Disease Control and Prevention|access-date=November 27, 2012}} Once in the gut of the sand fly, the parasites change from aflagelated amastigotes into flagellated promastigotes for one to two weeks until they are fully developed, a which point they make their way to the proboscis.

File:Leishmaniasis life cycle diagram en.svg

Upon biting a mammalian host, promastigotes are released into the bloodstream, where they are engulfed by macrophages. Following engulfment, promastigotes differentiate into amastigotes. Amastigotes are oval or round, and have a diameter between 2 and 3 μm.{{cite book|last=Guerrant|first=Richard L.|title=Tropical Infectious Diseases: Principles, Pathogens, & Practice|year=2006|publisher=Elsevier |isbn=9780443066689|pages=1095–1113|edition=2nd|author2=Walker, David H. |author3=Weller, Peter F. }} Additionally, they contain a large, eccentrically placed nucleus along with a kinetoplast (which holds extracellular DNA). Being equipped to survive the acidic environment inside the phagosomes of macrophages, the amastigotes reproduce through the process of binary fission. At this point the amastigotes are released throughout the body, and can be ingested by female sand flies, thus completing the cycle. L. major has a sexual cycle, including a meiotic process.{{cite journal |vauthors=Akopyants NS, Kimblin N, Secundino N, Patrick R, Peters N, Lawyer P, Dobson DE, Beverley SM, Sacks DL |title=Demonstration of genetic exchange during cyclical development of Leishmania in the sand fly vector |journal=Science |volume=324 |issue=5924 |pages=265–8 | date=April 2009 |pmid=19359589 |pmc=2729066 |doi=10.1126/science.1169464 |bibcode=2009Sci...324..265A }} Mating only occurs in the sand fly vector.{{cite journal |vauthors=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 |title=The mating competence of geographically diverse Leishmania major strains in their natural and unnatural sand fly vectors |journal=PLOS Genet. |volume=9 |issue=7 |pages=e1003672 |year=2013 |pmid=23935521 |pmc=3723561 |doi=10.1371/journal.pgen.1003672 |doi-access=free }}

Meriones unguiculatus, other Meriones and jirds, and other rodents are common hosts. Dogs,{{cite web | url=http://www.cfsph.iastate.edu/Factsheets/pdfs/leishmaniasis.pdf | title=Leishmaniasis | date=August 2017 | author1=Iowa State University | author2=Institute for Cooperation in Animal Biologics | author3=Iowa State University College of Veterinary Medicine | author4=OIE Collaborating Centre for Diagnosis of Animal Disease and Vaccine Evaluation in the Americas | author5=OIE Collaborating Centre for Day-One Veterinary Competencies and Continuing Education | author6=United States Department of Agriculture}}{{cite book | author=International Office of Epizootics Biological Standards Commission | title=Manual of Diagnostic Tests and Vaccines for Terrestrial Animals (mammals, birds and bees) | publication-place=Paris | pages=1–13 | chapter=3.1.11 Leishmaniosis | url=http://www.oie.int/en/what-we-do/standards/codes-and-manuals/terrestrial-manual-online-access/ | date=May 2021}}{{rp|page=2}} Mustela nivalis, Atelerix algirus, and Paraechinus aethiopicus are rare hosts. Mice are natural hosts.{{cite journal | last1=Sacks | first1=David | last2=Noben-Trauth | first2=Nancy | title=The immunology of susceptibility and resistance to Leishmania major in mice | journal=Nature Reviews Immunology | publisher=Nature Portfolio | volume=2 | issue=11 | year=2002 | issn=1474-1733 | doi=10.1038/nri933 | pages=845–858| pmid=12415308 | s2cid=12902476 | doi-access=free }} Transmission between mice is via Phlebotomus papatasi.

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.{{cite journal|last=Etges|first=R|author2=Bouvier J |author3=Bordier C |title=The major surface protein of Leishmania promastigotes is a protease|journal=J Biol Chem |issue=20 |pmid=3522584 |year=1986|volume=261|pages=9098–9101 |url=https://www.jbc.org/article/S0021-9258(18)67621-5/pdf |doi=10.1016/s0021-9258(18)67621-5|s2cid=38584080|doi-access=free}}{{cite journal|last=King|first=DL|author2=Chang Y-D |author3=Turco SJ |title=Cell surface lipophosphoglycan of Leishmania donovani|journal=Molecular and Biochemical Parasitology|year=1987|volume=24|pages=47–53|doi=10.1016/0166-6851(87)90114-9 |pmid=3614272 |issue=1}} 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. Activation of complements occurs far from the cell membrane, and insertion of the membrane attack complex does not occur. 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.{{cite journal | last=Innes | first=Elisabeth A. | title=The host-parasite relationship in pregnant cattle infected with Neospora caninum | journal=Parasitology | publisher=Cambridge University Press (CUP) | volume=134 | issue=13 | date=2007-10-25 | issn=0031-1820 | doi=10.1017/s0031182007000194 | pages=1903–1910| pmid=17958926 | s2cid=25927742 }} Neither cell type expresses exclusively IFNγ or IL-4 for L. major – Brown et al. 1998 find they express both in cattle. The bovine myeloid antimicrobial peptide {{visible anchor|BMAP-28}} has leishmanicidal activity and may be usable in vivo in cattle infection.{{cite journal | last1=Young-Speirs | first1=Morgan | last2=Drouin | first2=Dominique | last3=Cavalcante | first3=Paloma Araujo | last4=Barkema | first4=Herman W. | last5=Cobo | first5=Eduardo R. | title=Host defense cathelicidins in cattle: types, production, bioactive functions and potential therapeutic and diagnostic applications | journal=International Journal of Antimicrobial Agents | publisher=International Society of Antimicrobial Chemotherapy (Elsevier) | volume=51 | issue=6 | year=2018 | issn=0924-8579 | doi=10.1016/j.ijantimicag.2018.02.006 | pages=813–821| pmid=29476808 | s2cid=3518660 }} 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.

Dimethylallyltranstransferase is vital to L. major, making it an interesting target for leishmaniacidal substances.{{cite journal | last1=Vermelho | first1=Alane B. | last2=Capaci | first2=Giseli R. | last3=Rodrigues | first3=Igor A. | last4=Cardoso | first4=Verônica S. | last5=Mazotto | first5=Ana Maria | last6=Supuran | first6=Claudiu T. | title=Carbonic anhydrases from Trypanosoma and Leishmania as anti-protozoan drug targets | journal=Bioorganic & Medicinal Chemistry | publisher=Elsevier | volume=25 | issue=5 | year=2017 | issn=0968-0896 | doi=10.1016/j.bmc.2017.01.034 | pages=1543–1555| pmid=28161253 }} Propenko et al. 2014 present and validate several dimethylallyltranstransferase inhibitors.

File:Parasite130072-fig1 Map of cutaneous leishmaniasis in North Africa.tif

The incidence rate of cutaneous leishmaniasis is estimated to be between 1 and 1.5 million cases a year.{{cite journal|last=Desjeux|first=P|title=Human leishmaniasis: Epidemiology and public health aspects|journal=World Health Statistics Quarterly|year=1992|volume=45|pages=267–275 |pmid=1462660 |issue=2–3}} However, transmission does not often occur in utero, during blood transfusions, or through interpersonal contact. 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.{{cite book|title=The Merck Veterinary Manual|year=2005|publisher=Merial |location=Deluth, GA|isbn=0-911910-50-6|pages=643–644; 717|edition=9th|editor=Kahn, Cynthia M. |editor2=Line, Scott.}} Furthermore, because of the propensity of sand flies to seek out shelter in the burrows of small rodents, where L. major is endemic, small mammals such as gerbils and birds serve as the main reservoirs. Dogs have also been documented as contracting cutaneous leishmaniasis in Egypt{{cite journal |vauthors=Morsy TA, Schnur LF, Feinsod FM, Salem AM, Wahba MM, el Said SM |title=Natural infections of Leishmania major in domestic dogs from Alexandria, Egypt |journal=Am J Trop Med Hyg |volume=37 |issue=1 |pages=49–52 |date=1987 |doi=10.4269/ajtmh.1987.37.49 |pmid=3605504}} and Saudi Arabia.{{cite book|title=Dogs, Zoonoses and Public Health|url=https://archive.org/details/dogszoonosespubl00macp|url-access=limited|year=2000|publisher=CABI |location=New York, NY|isbn=0-85199-436-9|pages=[https://archive.org/details/dogszoonosespubl00macp/page/n150 139]|veditors=Macpherson CN, Meslin FX, Wandeler AI }} 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.{{cite journal |author=Centers for Disease Control and Prevention (CDC) |title=Update: Cutaneous leishmaniasis in U.S. military personnel—Southwest/Central Asia, 2002–2004 |journal=MMWR Morb Mortal Wkly Rep |volume=53 |issue=12 |pages=264–5 |date=2004 |pmid=15057192 |url=https://www.cdc.gov/mmwr/preview/mmwrhtml/mm5312a4.htm}}

File:Leishmaniose cutanée - Guyane fr.JPG

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. As more and more phagocytic cells engulf promastigotes, prompting the production of amastigotes, nodules form on the skin. These nodules then ulcerate, although due to the variable characteristics of the lesions, species specific identification of the pathogen is impossible. 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." 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.{{cite journal|last=Ridley|first=DS|title=The pathogenesis of cutaneous leishmaniasis|journal=Transactions of the Royal Society of Tropical Medicine and Hygiene|year=1979|volume=73|pages=150–160|doi=10.1016/0035-9203(79)90199-8 |pmid=473304 |issue=2}}

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.

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.

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. A number of different treatments have yielded results of varying effectiveness in the treatment of L. major caused cutaneous leishmaniasis.

• Fluconazole given in 200 mg doses over the course of 6 weeks resulted in 90% cure rate versus 60% in those given a placebo.{{cite journal|last=Alrajhi|first=AA|author2=Ibrahim EA |author3=De Vol EB |title=Fluconazole for the treatment of cutaneous leishamaniasis caused by Leishmania major|journal=The New England Journal of Medicine|year=2002|volume=346|issue=12|pages=891–895|doi=10.1056/nejmoa011882|display-authors=etal|pmid=11907288|doi-access=free}}
• Topical application of 15% paromomycin and 12% methylbenzethonium has been used successfully to treat patients in Israel.{{cite journal |vauthors=el-On J, Halevy S, Grunwald MH, Weinrauch L |title=Topical treatment of Old World cutaneous leishmaniasis caused by Leishmania major: a double-blind control study |journal=J Am Acad Dermatol |volume=27 |issue=2 Pt 1 |pages=227–231 |date=1992 |doi=10.1016/0190-9622(92)70175-f |pmid=1430361}}
• Intralesional injections of 0.5–2.0 mL of 100 mg/ML antimony has also been shown to be effective when injected around the sides of lesions. When 10 such injections were given to patients in Egypt, 85% were cured within 3 months.

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. Sand flies usually bite between dusk and dawn, so preventative measures should be taken during these times.

Though a vaccine does not yet exist that can prevent cutaneous leishmaniasis, it is speculated that one will be developed in the near future. Patients who have recovered from L. major infections develop high- level immunity to the pathogen. 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.

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Category:Parasitic excavates

Category:Trypanosomatida

Category:Euglenozoa species

Category:Protists described in 1914