TrypanosomiasisSleeping Sickness

David Humber

Trypanosomes of Vertebrates

T.corvi Corvids

T.cruzi Humans, rodents, marsupials

T.brucei sp Man, ungulatesT.lewisi RodentsT.musculis RodentsT.microti VolesT.dionisii BatsT.equiperdum Equids

Bone MarrowHeart muscle, autonomic

gangliaBloodBloodBloodLymphoid tissueHeart muscleGenitals

Species Host Site

African Sleeping SicknessNgana

South American Sleeping SicknessChagas Disease

African Sleeping Sickness

Parasite - Trypanosoma brucei ssp• Trypanosoma brucei rhodesiense• Trypanosoma brucei gambiense

Vector - Tse Tse fly• Glossina mortisans (Eastern Africa)• Glossina palpalis (Western Africa)

Lecture Topics

The Parasite & Vector The Life Cycle Clinical Features Diagnosis Epidemiology Chemotherapy & Control Vaccination

Taxonomy

Phylum Sub-Phylum Class Order Genus

MastigophoraSarcomastigophoraZoomastigophoraKinetoplastidaeTrypanosoma

? species of mammals, birds, reptiles and amphibians

The Parasite

Polymorphic spindle-shaped Kinetoplast Flagella & undulating membrane

TrypomastigoteEpimastigote

African TrypanosomiasisThe Life Cycle

Human Tse fly

Trypomastigote TrypomastigoteStumpy MetacyclicIntermediate EpimastigoteSlender Trypomastigote

The Vectors

Glossina22 species - hatchet wing cell

Shady habitat (20-30oC)Viviparous - 12 offspring

Diurnal feeders (1mg/sec)Parasite development 10-14 days

Animal Reservoirs

Sub species now thought to be zoonotic

Largely ungulates

African Sleeping Sickness

Virulence Reservoir Zoonotic Vector Distributi

on

Less MoreHuman/animal

Human/animalLess MoreG.palpalis

G.mortisansWestern Africa Eastern

Africa

T.b.gambiense T.b.rhodesiense

Clinical Features

Primary chancre - resolves 2-3 weeks

Initial symptoms - fever & headaches

Day time sleepingTremors & Convulsions

Coma & DeathEnlarged cervical lymph nodes (T.b.g)Winterbottoms sign

Diagnosis

Direct microscopy• Blood (T.b.r.)• Lymph node aspirate (T.b.g.)• Lumbar puncture (Late T.b.r. & T.b.g.)

Serology Animal inoculation

Epidemiology

50 million at risk<20% under surveillance

20,000 new case/yearDevastating epidemics

200 endemic foci

Distribution

Chemotherapy

Early stage - most recover• Suramin• Melasporol• Pentamidine

Late stage - upto 5% relapse• Only Melasporol

– 10% encephalitis - 5% fatal

Control

Destruction of animal reservoirVector Control

Diagnosis & treatment

Immunology

Antibody Inteferon

Parasitemia

Parasitemia in African Sleeping Sickness

0

2

4

6

8

10

0 10 20 30

Days after Infection

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Variable Surface Glycoprotein

60kd (450aa) glycoprotein (CHO 7-17%) C-terminal anchored in membrane

Often as a dimer (alpha helix)Densely clustered 107molecules/parasiteOnly epitopes in end third of N-terminal

exposedPresented as topographical array

T-independent antigen

VSG

Constant & Variable regionsRandom rearrangement of N terminal end

(2/3)Almost no homology between V VSG’s

Except cystein residues S-S bondsSwitching not initiated by IR

But selected

Production of VSG

Gene rearrangementProduces on expression linked copy (ELC)

ELC transposed to telomeric end of chromosome - replacing existing gene

Displaced gene lostSwitch occurs every 106 divisions

100-1000 copie of different VSG’s in clone

VSG Specific IR

3-4 days post infection strong IgM response

Trypanosome disappear within hoursVSG specific IgG appears - not relevant

IgM response often >IgGAfter several cycles VSG abs vanish

But abs to invariant ags remain elevated

Trypanosome Elimination

Antibody mediatedDestruction by Kupffer cells

Splenic macrophages minor role (cf malaria)

Uptake - C3b - C3bi - direct?C mediated lysis not important

Trypanosome destroyed within minutes

Immunoregulation

No secondary response to VSG’s unless cured by chemotherapy

Failure of 1ry or 2ndry response prior to death

Non specific polyclonal activationSuppresser MacrophagesFailure of Ag presentationAnti idiotype responses

Resistance and Virulence

Spectrum of diseaseT. brucei sub species

Host differencesIndependant of VSG

Vaccination

Effective Antibody responsePhagocytosis & killing

butCyclical parasitemia

Antigenic variation not predicable