leishmaniasis david p. humber department of life sciences university of east london
TRANSCRIPT
Leishmaniasis
David P. Humber
Department of Life Sciences
University of East London
Lecture Topics
• The parasite and vector
• The life-cycle
• Clinical features
• Diagnosis
• Epidemiology
• Chemotherapy
• Vaccination
Introduction
Leishmaniasis
Protozoal disease of mammals
Largely zoonotic
23+ pathogenic species
Cutaneous leishmaniasis
Visceral Leishmaniasis
The Parasite• Phylum
• Order
• Family
• Genus
Sarcomastigophora
Kinetoplastida
Trypanosomatidae
Leishmania
Morphology
• Promasitogte– Insect
– Motile
– Midgut
• Amastigote– Mammalian stage
– Non-motile
– Intracellular
Digenetic Life Cycle
Morphology• Promastigote • Amastigote
Flagella
Kinetoplast
Golgi
Nucleus
Cytoskeleton
Scanning EM of Promastigote Rosette
Promastigote in Culture
Kinetoplast
Nucleus
Scanning EM TIA
Amastigotes - skin biopsy
Speciation
• Similar morphology
• DNA bouyant density
• Isoenzyme profiles - Zymodemes
• Monoclonal antibodies
• DNA hybridisation - PCR
Species Pathogenic in Humans
• Leishmania aethiopica
• Leishmania brazilliensis (complex)
• Leishmania donovani (complex)
• Leishmania major
• Leishmania mexicana (complex)
• Leishmania tropica
Mammalian Hosts• Rodents• Gerbils• Hyraxes• Bats• Porcupines• Opossums
• Sloths• Primates• Dogs• Foxes• Anteaters• . . . . .
Canine Host
Procavia capensis
Sloth Host
Distribution of Leishmaniasis
Vectors
Phlebotomine Sandflies
6 genera world wide distribution
Phlebotomus & Lutzomia
500 species
Females Haematophagus
Males sap feeders
Sandfly - Phlebotomous pedifer
Clinical Disease• Visceral
– Fatal (90% untreated)
– Liver
– Spleen
– Bone marrow
• Cutaneous– Generally Self- healing
– Skin
– Mucous membranes
SPECTRUM OF DISEASE
Initial Infection
• Similar in all species
• Inoculation of promastigotes
• Inflammation & chemotaxis
• Receptor mediated phagocytosis
Promastigote Amasitgote Transformation
Parasite Spread
Macrophage lysis & parasite release
Lymphatic spread
Blood spread
Target organs
Skin/lymph nodes/spleen/liver/bone marrow
Visceral Leishmaniasis• 1903• 1920• 1931
William Leishman
Pentavalent antimony
Experimental transmission
Leishmania donovani (complex)
L.d. archibaldi - L.d.chagasi L.d.donovani - Ld.infantum
VL - Clinical Symptoms
Variable - Incubation 3-100+ weeks
Lowgrade fever
Hepato-splenomegaly
Bone marrow hyperplasia
Leucopenia & Cachexia
Hypergammaglobulinnemia
Visceral Leishmaniasis
Epidemiology - Distribution
INFECTIONSub-clinical or inapparent infection
Recovery DeathImmune to reinfection Concurrent infection
PKDL
Post Kala Azar Dermal Leishmanoid
Normally develops <2 years after recovery
Recrudescence
Restricted to skin
Rare but varies geographically
Diagnosis
Clinical signs & symptoms
HypergammaglobulinemiaELISA/Formol gel
Bone marrow biopsy
Spleen or liver biopsy
Culture & Histology
Biopsy punch
Specificity of L. aethiopica primers
• Marker
• L.. aethiopica
• L. tropica
• L. major
• L.. donovani
Treatment
Good nursing & Diet
Antibiotics
Pentavalent antimony (upto 25% ressistance)
Pentamidine
Amidosidine
New drugs - New delivery
Immune Response
Innate IRs– Lsh/BCG gene
• Lshr Lshs
– No real human equivalent– Other species specific genes described– Complement– Polymorphs– Macrphages
Macrophages
• Receptors– CR3 receptors for C3bi– Lipophosphoglycan– GP63
• Killing• Oxygen dependent• Oxygen independent
Macrophage activation
• T cell activation– TH - 1 IL2, Gamma interferon– TH - 2 IL4, IL5
• SALT– Langerhans cells– Tissue dendritic cells
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
CL - Cutaneous Leishmaniasis
• Old World– Leishmania aethiopica
– Leishmania major
– Leishmania tropica
• New World– Leishmania brazillensis
• L.b.
• L.b.
– Leishmania mexicana• L.m
• L.m
SpectrumLCL - MCL - DCL
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
Localised Cutaneous Leishmaniasis
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
Mucocutaneous Leishmaniasis
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
Diffuse Cutaneous Leishmaniasis
Uta
EpidemiologyOld World
EpidemiologyNew World
Diagnosis
Clinical feature & geographical location
Skin biopsy/slit skin smear
Culture & histology
Monoclonal antibodies
PCR
Treatment
Control secondary infection
Self-healing - probably no treatment
Surgery/cryosurgery/Topical
MCL & DCL
Pentavalent antimony - pentamidine
Control
• Vector control
• Reservoir control
• Treatment of active cases
• Vaccination