1. We work with the protozoan parasite Leishmania… Leishmania

2. Discovery of the infectious agent 1921:extracel. promastigote 1900: intracellular amastigote William LeishmanCharles Donovan Edmond SergentEtienne Sergent Leishmania Med Mol Para 2

3. 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 3

4. Introduction Leishmania 4 According to disease burden estimates, leishmaniasis ranks third in disease burden in disability-adjusted life years caused by neglected tropical diseases and is the second cause of parasite-related deaths after malaria Med Mol Para

5. Disability adjusted life years lost WHO RegionDALY (in thousands) Africa328 Americas45 Eastern Mediterranean281 Southeast Asia1,264 Western Pacific51 Total:1,969 DALY: Number of years lost due to ill health disability or death Leishmania 5 Med Mol Para

6. Leishmania 6 Med Mol Para

7. Leishmania 7 Med Mol Para

8. Leishmania 8 Med Mol Para

9. Leishmania: a digenetic life cycle 9 Med Mol Para

10. Leishmania: a digenetic life cycle 10 Med Mol Para

11. 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 Med Mol Para

12. Leishmania: a digenetic life cycle 12 Med Mol Para Forestier et al, (2011) Cell Host Microbe

13. Jericho boil Aleppo boil oriental sore L. major Leishmaniasis cutaneous Burdwan fever Shahib's disease kala-azar L. donovani visceral L. tropica chiclero ulcer espundia Andean sickness uta white leprosy L. braziliensis L. mexicana muco-cutaneous 13 Med Mol Para

14. 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 Med Mol Para

15. Diffuse Cutaneous Leishmaniasis L. aethiopica L. mexicana L. venezuelensis L. amazonensis http://www.emedicine.com/DERM/topic219.htm 15 Types of Leishmaniasis Leishmaniasis Med Mol Para

16. Recidivans Cutaneous Leishmaniasis L. tropica L. braziliensis http://www.emedicine.com/DERM/topic219.htm 16 Leishmaniasis 16 Med Mol Para

17. Mucocutaneous Leishmaniasis L. major L. aethiopica L. mexicana L. amazonensis L. braziliensis L. panamensis L. guyanensis Leishmaniasis Med Mol Para

18. Visceral Leishmaniasis L. donovani L. tropica L. infantum 18 Leishmaniasis Med Mol Para

19. Leishmaniasis Amazon India Med Mol Para

20. 20 Leishmaniasis Afghan Med Mol Para

21. Leishmaniasis Afghan Med Mol Para

22. 22 Leishmaniasis Nepal Med Mol Para

23.  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 23 Med Mol Para

24. 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 24 Med Mol Para

25. Treatment Antifungal 25 Med Mol Para

26. 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. 26 http://www.youtube.com/watch?v=yr-01IPiz0g Med Mol Para

27. Vaccine No successful vaccine. There are several first generation and second generation vaccines which are under clinical trial. 1 st gen: use whole molecular organism 2 nd 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. 27 Med Mol Para

28. Preventions Vector control intervention. Insecticidal treated nets. Indoor residual spraying. Screening windows. Wearing insect repellents. Wearing protective clothing. 28 Med Mol Para