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We work with the protozoan parasite Leishmania

Leishmania

Discovery of the infectious agent

1921:extracel. promastigote

1900: intracellular amastigoteWilliam LeishmanCharles Donovan

Edmond Sergent

Etienne Sergent

Leishmania Med Mol Para

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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 Med Mol Para

33Introduction

Leishmania

4According 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 malariaMed Mol Para

Disability adjusted life years lostWHO RegionDALY (in thousands)Africa328Americas45Eastern Mediterranean281Southeast Asia1,264Western Pacific51Total:1,969DALY: Number of years lost due to ill health disability or death

Leishmania 5Med Mol Para

Leishmania 6

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Leishmania: a digenetic life cycle

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Leishmania: a digenetic life cycle10Med Mol Para

Procyclic promastigote - LPG with galactose branching sugars- Able to bind midgut epithelium- non-infective stageMetacyclic promastigote- LPG with arabinose substituting galactose- LPG increases in size (Gal-Man-PO4) repetitive units- Not able to bind to midgut epithelium- Infective stagePimenta et al (1992) Science 256:1812-181511http://www.youtube.com/watch?v=-HY_LbzQ9i4

Stage specific adhesion of Leishmania promastigotes to the Sand fly midgutMed Mol Para

Leishmania: a digenetic life cycle12Med Mol Para

Forestier et al, (2011) Cell Host Microbe Jericho boilAleppo boil oriental sore

L. major

Leishmaniasiscutaneous

Burdwan fever Shahib's diseasekala-azar

L. donovanivisceral

L. tropicachiclero ulcerespundiaAndean sicknessutawhite leprosy

L. braziliensisL. mexicanamuco-cutaneous

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Localized Cutaneous LeishmaniasisL. majorL. tropicaL. aethiopicaL. infantumL. mexicanaL. venezuelensisL. amazonensisL. braziliensisL. panamensisL. guyanensisL. peruvianaL. chagasi

Leishmaniasis Med Mol Para

Diffuse Cutaneous LeishmaniasisL. aethiopicaL. mexicanaL. venezuelensisL. amazonensishttp://www.emedicine.com/DERM/topic219.htm

15 Types of Leishmaniasis

LeishmaniasisMed Mol Para

Recidivans Cutaneous LeishmaniasisL. tropicaL. braziliensishttp://www.emedicine.com/DERM/topic219.htm

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Leishmaniasis16Med Mol Para

Mucocutaneous LeishmaniasisL. majorL. aethiopicaL. mexicanaL. amazonensisL. braziliensisL. panamensisL. guyanensis

LeishmaniasisMed Mol Para

Visceral LeishmaniasisL. donovaniL. tropicaL. infantumL. infantum

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LeishmaniasisMed Mol Para

Leishmaniasis

Amazon

IndiaMed Mol Para

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Leishmaniasis

AfghanMed Mol Para

Leishmaniasis

AfghanMed Mol Para

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Leishmaniasis

NepalMed Mol Para

Symptoms of cutaneous leishmaniasis :Breathing difficultySkin sores, which may become a skin ulcer that heals very slowlyStuffy nose, runny nose, and nosebleedsSwallowing difficultyUlcers and wearing away (erosion) in the mouth, tongue, gums, lips, nose, and inner nose

Systemic visceral infection in children usually begins suddenly with:CoughdiarrheaFeverVomiting Symptoms

Abdominal discomfortFever that lasts for weeks; may come and go in cyclesNight sweatsScaly, gray, dark, ashen skinThinning hairWeight lossADULTS

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.

Diagnosis2424Med Mol Para

Treatment

Antifungal252525Med Mol Para

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.262626http://www.youtube.com/watch?v=yr-01IPiz0gMed Mol Para

VaccineNo successful vaccine.

There are several first generation and second generation vaccines which are under clinical trial.1st gen: use whole molecular organism2nd 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.

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Preventions

Vector control intervention.

Insecticidal treated nets.

Indoor residual spraying.

Screening windows.

Wearing insect repellents.

Wearing protective clothing.2828282828Med Mol Para