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Leishmaniasis

Leishmaniasis

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Leishmaniasis

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  1. Leishmaniasis David P. Humber Department of Life Sciences University of East London

  2. Lecture Topics • The parasite and vector • The life-cycle • Clinical features • Diagnosis • Epidemiology • Chemotherapy • Vaccination

  3. Introduction Leishmaniasis Protozoal disease of mammals Largely zoonotic 23+ pathogenic species Cutaneous leishmaniasis Visceral Leishmaniasis

  4. Phylum Order Family Genus Sarcomastigophora Kinetoplastida Trypanosomatidae Leishmania The Parasite

  5. Promasitogte Insect Motile Midgut Amastigote Mammalian stage Non-motile Intracellular Morphology Digenetic Life Cycle

  6. Promastigote Amastigote Morphology Flagella Kinetoplast Golgi Nucleus Cytoskeleton

  7. Scanning EM of Promastigote Rosette

  8. Kinetoplast Promastigote in Culture Nucleus

  9. Scanning EM TIA

  10. Amastigotes - skin biopsy

  11. Speciation • Similar morphology • DNA bouyant density • Isoenzyme profiles - Zymodemes • Monoclonal antibodies • DNA hybridisation - PCR

  12. Species Pathogenic in Humans • Leishmania aethiopica • Leishmania brazilliensis (complex) • Leishmania donovani (complex) • Leishmania major • Leishmania mexicana (complex) • Leishmania tropica

  13. Rodents Gerbils Hyraxes Bats Porcupines Opossums Sloths Primates Dogs Foxes Anteaters . . . . . Mammalian Hosts

  14. Canine Host

  15. Procavia capensis

  16. Sloth Host

  17. Distribution of Leishmaniasis

  18. Vectors Phlebotomine Sandflies 6 genera world wide distribution Phlebotomus & Lutzomia 500 species Females Haematophagus Males sap feeders

  19. Sandfly - Phlebotomous pedifer

  20. Visceral Fatal (90% untreated) Liver Spleen Bone marrow Cutaneous Generally Self- healing Skin Mucous membranes Clinical Disease SPECTRUM OF DISEASE

  21. Initial Infection • Similar in all species • Inoculation of promastigotes • Inflammation & chemotaxis • Receptor mediated phagocytosis Promastigote Amasitgote Transformation

  22. Parasite Spread Macrophage lysis & parasite release Lymphatic spread Blood spread Target organs Skin/lymph nodes/spleen/liver/bone marrow

  23. 1903 1920 1931 William Leishman Pentavalent antimony Experimental transmission Visceral Leishmaniasis Leishmania donovani (complex) L.d. archibaldi - L.d.chagasi L.d.donovani - Ld.infantum

  24. VL - Clinical Symptoms Variable - Incubation 3-100+ weeks Lowgrade fever Hepato-splenomegaly Bone marrow hyperplasia Leucopenia & Cachexia Hypergammaglobulinnemia

  25. Visceral Leishmaniasis

  26. Epidemiology - Distribution

  27. INFECTION Sub-clinical or inapparent infection RecoveryDeath Immune to reinfection Concurrent infection PKDL

  28. Post Kala Azar Dermal Leishmanoid Normally develops <2 years after recovery Recrudescence Restricted to skin Rare but varies geographically

  29. Diagnosis Clinical signs & symptoms Hypergammaglobulinemia ELISA/Formol gel Bone marrow biopsy Spleen or liver biopsy Culture & Histology

  30. Biopsy punch

  31. Marker L.. aethiopica L. tropica L. major L.. donovani Specificity of L. aethiopica primers

  32. Treatment Good nursing & Diet Antibiotics Pentavalent antimony (upto 25% ressistance) Pentamidine Amidosidine New drugs - New delivery

  33. Immune Response Innate IRs • Lsh/BCG gene • Lshr Lshs • No real human equivalent • Other species specific genes described • Complement • Polymorphs • Macrphages

  34. Macrophages • Receptors • CR3 receptors for C3bi • Lipophosphoglycan • GP63 • Killing • Oxygen dependent • Oxygen independent

  35. Macrophage activation • T cell activation • TH - 1 IL2, Gamma interferon • TH - 2 IL4, IL5 • SALT • Langerhans cells • Tissue dendritic cells

  36. Vaccines • Leishmania + BCG • Ecuador - 3 species (Lbb,Lbg,Lma) • 2 doses killed whole parasites • 70% protection • Iran - 1 species (Lt) • 1 dose whole killed • 35% responded • 0% cf BCG alone

  37. Old World Leishmania aethiopica Leishmania major Leishmania tropica New World Leishmania brazillensis L.b. L.b. Leishmania mexicana L.m L.m CL - Cutaneous Leishmaniasis Spectrum LCL - MCL - DCL

  38. Localised Cutaneous Leishmaniasis • Single or multiple lesions • Usually on head and/or neck • Generally self-healing • Variable few week to many months • Ulceration followed by healing & scar • Secondary infection & tissue erosion

  39. Localised Cutaneous Leishmaniasis

  40. Mucocutaneous Leishmaniasis • Direct inoculation or extension • L.aethiopica & others • Low cell mediated immunity (CMI) • Metastatic spread • L.b.brazilliensis • High CMI & extensive tissue destruction • Also in DCL but no MI no tissue damage

  41. Mucocutaneous Leishmaniasis

  42. Diffuse Cutaneous Leishmaniasis • Multiple diffuse spreading lesions • Usually face & limbs rarely trunk • No ulceration • Non-healing - life long infection • No cell mediated immunity • Good antibody response Leishmania aethiopica & Leishmania mexicana mexicana

  43. Diffuse Cutaneous Leishmaniasis

  44. Uta

  45. EpidemiologyOld World

  46. EpidemiologyNew World

  47. Diagnosis Clinical feature & geographical location Skin biopsy/slit skin smear Culture & histology Monoclonal antibodies PCR

  48. Treatment Control secondary infection Self-healing - probably no treatment Surgery/cryosurgery/Topical MCL & DCL Pentavalent antimony - pentamidine

  49. Control • Vector control • Reservoir control • Treatment of active cases • Vaccination