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