We work with the protozoan parasite Leishmania…

1. We work with the protozoan parasite Leishmania… Leishmania

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

3. Leishmania • 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 Med Mol Para

4. Leishmania Introduction 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. Leishmania Disability adjusted life years lost • DALY: Number of years lost due to ill health disability or death Med Mol Para

6. Leishmania Med Mol Para

7. Leishmania Med Mol Para

8. Leishmania Med Mol Para

9. Leishmania: a digenetic life cycle Med Mol Para

10. Leishmania: a digenetic life cycle Med Mol Para

11. Stage specific adhesion of Leishmania promastigotes to the Sand fly midgut Procyclic promastigote - LPG with galactose branching sugars - Able to bind midgut epithelium - non-infective stage Metacyclicpromastigote http://www.youtube.com/watch?v=-HY_LbzQ9i4 - 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 Med Mol Para

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

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

14. L. mexicana L. venezuelensis L. amazonensis L. braziliensis L. panamensis L. guyanensis L. peruviana L. chagasi Leishmaniasis L. major L. tropica L. aethiopica L. infantum Localized Cutaneous Leishmaniasis Med Mol Para

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

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

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

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

19. Leishmaniasis Amazon India Med Mol Para

20. Leishmaniasis Afghan Med Mol Para

21. Leishmaniasis Afghan Med Mol Para

22. Leishmaniasis Nepal Med Mol Para

23. Symptoms • 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 Children • 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 Med Mol Para

24. Diagnosis • 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. 24 Med Mol Para

25. Treatment Antifungal 25 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. http://www.youtube.com/watch?v=yr-01IPiz0g 26 26 Med Mol Para

27. 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. 27 27 27 Med Mol Para

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