Trypanosomiasis Sleeping Sickness

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TrypanosomiasisSleeping Sickness

• David Humber

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Trypanosomes of Vertebrates
Species Host Site

• T.corvi Corvids
• T.cruzi Humans, rodents,
  marsupials
• T.brucei sp Man, ungulates
• T.lewisi Rodents
• T.musculis Rodents
• T.microti Voles
• T.dionisii Bats
• T.equiperdum Equids

• Bone Marrow
• Heart muscle,
• autonomic ganglia
• Blood
• Blood
• Blood
• Lymphoid tissue
• Heart muscle
• Genitals

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African Sleeping SicknessNganaSouth American
Sleeping SicknessChagas Disease
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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)

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Lecture Topics

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

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Taxonomy

• Phylum
• Sub-Phylum
• Class
• Order
• Genus

• Mastigophora
• Sarcomastigophora
• Zoomastigophora
• Kinetoplastidae
• Trypanosoma

? species of mammals, birds, reptiles and
amphibians
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The Parasite

• Polymorphic spindle-shaped
• Kinetoplast
• Flagella undulating membrane

Trypomastigote Epimastigote
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African TrypanosomiasisThe Life Cycle

• Human Tse fly
• Trypomastigote Trypomastigote
• Stumpy Metacyclic
• Intermediate Epimastigote
• Slender Trypomastigote

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The Vectors

• Glossina
• 22 species - hatchet wing cell
• Shady habitat (20-30oC)
• Viviparous - 12 offspring
• Diurnal feeders (1mg/sec)
• Parasite development 10-14 days

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Animal Reservoirs

• Sub species now thought to be zoonotic
• Largely ungulates

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African Sleeping Sickness
T.b.gambiense T.b.rhodesiense

• Virulence
• Reservoir
• Zoonotic
• Vector
• Distribution

• Less More
• Human/animal Human/animal
• Less More
• G.palpalis G.mortisans
• Western Africa Eastern Africa

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Clinical Features

• Primary chancre - resolves 2-3 weeks
• Initial symptoms - fever headaches
• Day time sleeping
• Tremors Convulsions
• Coma Death

Enlarged cervical lymph nodes (T.b.g) Winterbottom
s sign
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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

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Epidemiology

• 50 million at risk
• lt20 under surveillance
• 20,000 new case/year
• Devastating epidemics
• 200 endemic foci

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Distribution
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Chemotherapy

• Early stage - most recover
• Suramin
• Melasporol
• Pentamidine
• Late stage - upto 5 relapse
• Only Melasporol
• 10 encephalitis - 5 fatal

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Control

• Destruction of animal reservoir
• Vector Control
• Diagnosis treatment

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Immunology

• Antibody
• Inteferon

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Parasitemia
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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/parasite
• Only epitopes in end third of N-terminal exposed
• Presented as topographical array
• T-independent antigen

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VSG

• Constant Variable regions
• Random rearrangement of N terminal end (2/3)
• Almost no homology between V VSGs
• Except cystein residues S-S bonds
• Switching not initiated by IR
• But selected

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Production of VSG

• Gene rearrangement
• Produces on expression linked copy (ELC)
• ELC transposed to telomeric end of chromosome -
  replacing existing gene
• Displaced gene lost
• Switch occurs every 106 divisions
• 100-1000 copie of different VSGs in clone

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VSG Specific IR

• 3-4 days post infection strong IgM response
• Trypanosome disappear within hours
• VSG specific IgG appears - not relevant
• IgM response often gtIgG
• After several cycles VSG abs vanish
• But abs to invariant ags remain elevated

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Trypanosome Elimination

• Antibody mediated
• Destruction by Kupffer cells
• Splenic macrophages minor role (cf malaria)
• Uptake - C3b - C3bi - direct?
• C mediated lysis not important
• Trypanosome destroyed within minutes

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Immunoregulation

• No secondary response to VSGs unless cured by
  chemotherapy
• Failure of 1ry or 2ndry response prior to death
• Non specific polyclonal activation
• Suppresser Macrophages
• Failure of Ag presentation
• Anti idiotype responses

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Resistance and Virulence

• Spectrum of disease
• T. brucei sub species
• Host differences
• Independant of VSG

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Vaccination

• Effective Antibody response
• Phagocytosis killing
• but
• Cyclical parasitemia
• Antigenic variation not predicable