We work with the protozoan parasite Leishmania…Leishmania

Discovery of the infectious agent

1921:extracel. promastigote1900: intracellular amastigote

William Leishman Charles Donovan Edmond Sergent Etienne Sergent

Leishmania

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• 88 countries/350 million at risk

• 12 million cases/2 million new infected

• 57,000 deaths annually/4 million DALY

• second to malaria in mortality and disability

• synergy with HIV co-infection

• no vaccine, limited treatment

• emerging disease

Leishmania

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IntroductionLeishmania

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According to disease burden estimates, leishmaniasis ranks third in disease burden in disability-adjusted life years caused by neglectedtropical diseases and is the second cause of parasite-related deaths after malaria

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Disability adjusted life years lostWHO Region DALY (in thousands)

Africa 328

Americas 45

Eastern Mediterranean 281

Southeast Asia 1,264

Western Pacific 51

Total: 1,969

• DALY: Number of years lost due to ill health disability or death

Leishmania

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Leishmania

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Leishmania

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Leishmania

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Leishmania: a digenetic life cycle

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Leishmania: a digenetic life cycle

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Procyclic promastigote

- LPG with galactose branching sugars

- Able to bind midgut epithelium

- non-infective stage

Metacyclic promastigote- LPG with arabinose substituting galactose

- LPG increases in size (Gal-Man-PO4) repetitive units

- Not able to bind to midgut epithelium

- Infective stage

Pimenta et al (1992) Science 256:1812-1815 11

http://www.youtube.com/watch?v=-HY_LbzQ9i4

Stage specific adhesion of Leishmania promastigotes to the Sand fly midgut

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Leishmania: a digenetic life cycle

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Forestier et al, (2011) Cell Host Microbe

Jericho boil

Aleppo boil

oriental sore

L. major

Leishmaniasis

cutaneous

Burdwan fever

Shahib's disease

kala-azar

L. donovani

visceral

L. tropica

chiclero ulcerespundia

Andean sickness

uta

white leprosy

L. braziliensis

L. mexicana

muco-cutaneous

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Localized Cutaneous Leishmaniasis

L. major

L. tropica

L. aethiopica

L. infantum

L. mexicana

L. venezuelensis

L. amazonensis

L. braziliensis

L. panamensis

L. guyanensis

L. peruviana

L. chagasi

Leishmaniasis

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Diffuse Cutaneous Leishmaniasis

L. aethiopica

L. mexicana

L. venezuelensis

L. amazonensis

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Types of Leishmaniasis Leishmaniasis

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Recidivans Cutaneous Leishmaniasis

L. tropica

L. braziliensis

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Leishmaniasis

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Mucocutaneous Leishmaniasis

L. major

L. aethiopica

L. mexicana

L. amazonensis

L. braziliensis

L. panamensis

L. guyanensis

Leishmaniasis

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Visceral Leishmaniasis

L. donovani

L. tropica

L. infantum

L. infantum

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Leishmaniasis

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Leishmaniasis

Amazon

India

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Leishmaniasis

Afghan

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Leishmaniasis

Afghan

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Leishmaniasis

Nepal

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Symptoms of cutaneous leishmaniasis :• Breathing difficulty• Skin sores, which may become a skin ulcer that heals very slowly• Stuffy nose, runny nose, and nosebleeds• Swallowing difficulty• Ulcers and wearing away (erosion) in the mouth, tongue, gums, lips, nose, and inner nose

Systemic visceral infection in children usually begins suddenly with:• Cough• diarrhea• Fever• Vomiting

Symptoms

• Abdominal discomfort• Fever that lasts for weeks; may come and go in cycles• Night sweats• Scaly, gray, dark, ashen skin• Thinning hair• Weight loss

ADULTS

Children

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• Direct visualization of amastigotes by hematological staining doing tissue biopsy.

• Enzyme linked Immunosorbent assay (ELISA).

• Antigen coated dipsticks.

• Direct agglutination test.

• Leishmania specific PCR assay.

• Indirect Immunofluorescent antibody test.

• Complete blood count.

Diagnosis

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Treatment

Antifungal

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Treatment

Miltefosine • First oral drug against leishmaniasis.• Originally developed for cancer.• Used in the case of visceral and cutaneous leishmaniasis.• Also target HIV infected macrophages.• Inhibit PI3K/AKT pathways.

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http://www.youtube.com/watch?v=yr-01IPiz0g

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Vaccine

• No successful vaccine.

• There are several first generation and second generation vaccines which are under clinical trial.• 1st gen: use whole molecular organism• 2nd gen: recombinant protein grown in bacteria; purified; then, take vaccine of

that purified vaccine.

• LACK antigen (Leishmania homologue of receptor for activated C kinase).

• LEISH-F1+MPL-SE Vaccine (Second generation vaccine) was in clinical trial for its safety and immunogenicity (2011). Presently under clinical development.

• Infectious Disease Research Institute launched two phase-1 clinical trial of vaccine against visceral Leishmaniasis. 272727Med Mol Para

Preventions

• Vector control intervention.

• Insecticidal treated nets.

• Indoor residual spraying.

• Screening windows.

• Wearing insect repellents.

• Wearing protective clothing.

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