trypanosomiasis sleeping sickness david humber department of life sciences university of east london
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TrypanosomiasisSleeping Sickness
David HumberDavid Humber
Department of Life SciencesDepartment of Life Sciences
University of East LondonUniversity of East London
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Trypanosomes of Vertebrates
T.corviT.corvi CorvidsCorvids
T.cruziT.cruzi Humans, Humans, rodents, rodents, marsupialsmarsupials
T.brucei spT.brucei sp Man, ungulatesMan, ungulates
T.lewisiT.lewisi RodentsRodents
T.musculisT.musculis RodentsRodents
T.microtiT.microti VolesVoles
T.dionisiiT.dionisii BatsBats
T.equiperdumT.equiperdum EquidsEquids
Bone MarrowBone Marrow
Heart muscle,Heart muscle,
autonomic autonomic gangliaganglia
BloodBlood
BloodBlood
BloodBlood
Lymphoid tissueLymphoid tissue
Heart muscleHeart muscle
GenitalsGenitals
Species Host Site
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African Sleeping SicknessNgana
South American Sleeping SicknessChagas Disease
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African Sleeping Sickness
Parasite - Parasite - Trypanosoma brucei sspTrypanosoma brucei ssp• Trypanosoma brucei rhodesienseTrypanosoma brucei rhodesiense• Trypanosoma brucei gambienseTrypanosoma brucei gambiense
Vector - Tse Tse flyVector - Tse Tse fly• Glossina mortisans Glossina mortisans (Eastern Africa)(Eastern Africa)• Glossina palpalis Glossina palpalis (Western Africa)(Western Africa)
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Learning Outcomes
The Parasite & VectorThe Parasite & Vector The Life CycleThe Life Cycle Clinical FeaturesClinical Features DiagnosisDiagnosis EpidemiologyEpidemiology Chemotherapy & ControlChemotherapy & Control VaccinationVaccination
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Taxonomy
Phylum Phylum Sub-PhylumSub-Phylum ClassClass OrderOrder GenusGenus
MastigophoraMastigophora
SarcomastigophoraSarcomastigophora
ZoomastigophoraZoomastigophora
KinetoplastidaeKinetoplastidae
TrypanosomaTrypanosoma
? species of mammals, birds, reptiles and amphibians
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The Parasite
Polymorphic spindle-shapedPolymorphic spindle-shaped• Proliferative long-slenderProliferative long-slender• IntermediatesIntermediates• Non-proloiferative short-stumpyNon-proloiferative short-stumpy
KinetoplastKinetoplast Flagella & undulating membraneFlagella & undulating membrane
TrypomastigoteProcyclic
Epimastigote
Parasitemia
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African TrypanosomiasisThe Life Cycle
HumanHuman Tse flyTse fly
TrypomastigoteTrypomastigoteTrypomastigoteTrypomastigoteStumpyStumpy MetacyclicMetacyclic
IntermediateIntermediate EpimastigoteEpimastigote
SlenderSlender TrypomastigoteTrypomastigote
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The Vectors
GlossinaGlossina
22 species - hatchet wing cell22 species - hatchet wing cell
Shady habitat (20-30Shady habitat (20-30ooC)C)
Viviparous - 12 offspringViviparous - 12 offspring
Diurnal feeders (1mg/sec)Diurnal feeders (1mg/sec)
Parasite development 10-14 daysParasite development 10-14 days
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Animal Reservoirs
Sub species now thought to be Sub species now thought to be zoonoticzoonotic
Largely ungulatesLargely ungulates
Cattle & PigsWild game
Hyaena
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African Sleeping Sickness
VirulenceVirulence ReservoirReservoir ZoonoticZoonotic VectorVector DistributiDistributi
onon
LessLess More More
Human/animalHuman/animal Human/animalHuman/animal
LessLess More More
G.palpalisG.palpalis G.mortisansG.mortisans
Western AfricaWestern Africa Eastern Eastern AfricaAfrica
T.b.gambiense T.b.rhodesiense
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Clinical Features
Primary chancre - resolves 2-3 Primary chancre - resolves 2-3 weeksweeks
Initial symptoms - fever & Initial symptoms - fever & headachesheadaches
Day time sleepingDay time sleeping
Tremors & ConvulsionsTremors & Convulsions
Coma & DeathComa & DeathEnlarged cervical lymph nodes (T.b.g)Winterbottoms sign
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Diagnosis
Direct microscopyDirect microscopy• Blood (Blood (T.b.r.T.b.r.))• Lymph node aspirate (Lymph node aspirate (T.b.g.T.b.g.))• Lumbar puncture (Late Lumbar puncture (Late T.b.r. & T.b.r. &
T.b.g.T.b.g.)) SerologySerology Animal inoculationAnimal inoculation
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Epidemiology
50 million at risk50 million at risk
<20% under surveillance<20% under surveillance
20,000 new case/year20,000 new case/year
Devastating epidemicsDevastating epidemics
200 endemic foci200 endemic foci
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Distribution of Disease & Vector
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Chemotherapy
Early stage - most recoverEarly stage - most recover• SuraminSuramin• MelasporolMelasporol• PentamidinePentamidine
Late stage - upto 5% relapseLate stage - upto 5% relapse• Only Melasoprol & EflornithineOnly Melasoprol & Eflornithine
– 10% encephalitis - 5% fatal10% encephalitis - 5% fatal
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Control
Destruction of animal reservoirDestruction of animal reservoir
Vector ControlVector Control
Diagnosis & treatmentDiagnosis & treatment
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ParasitemiaParasitemia in African Sleeping
Sickness
0
2
4
6
8
10
0 10 20 30
Days after Infection
Lo
g 1
0 T
ryp
ano
so
me
s p
er
ml
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Variable Surface Glycoprotein
60kd (450aa) glycoprotein (CHO 7-17%) 60kd (450aa) glycoprotein (CHO 7-17%)
C-terminal anchored in membraneC-terminal anchored in membrane
Often as a dimer (alpha helix)Often as a dimer (alpha helix)
Densely clustered 10Densely clustered 1077molecules/parasitemolecules/parasite
Only epitopes in end third of N-terminal Only epitopes in end third of N-terminal exposedexposed
Presented as topographical arrayPresented as topographical array
T-independent antigenT-independent antigen
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VSG
Constant & Variable regionsConstant & Variable regions
Random rearrangement of N terminal end Random rearrangement of N terminal end (2/3)(2/3)
Almost no homology between V VSG’sAlmost no homology between V VSG’s
Except cystein residues S-S bondsExcept cystein residues S-S bonds
Switching not initiated by IRSwitching not initiated by IR
But selectedBut selected
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Production of VSG
Gene rearrangementGene rearrangement
Produces on expression linked copy (ELC)Produces on expression linked copy (ELC)
ELC transposed to telomeric end of ELC transposed to telomeric end of chromosome - replacing existing genechromosome - replacing existing gene
Displaced gene lostDisplaced gene lost
Switch occurs every 10Switch occurs every 1066 divisions divisions
100-1000 copie of different VSG’s in clone100-1000 copie of different VSG’s in clone
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VSG Specific IR
3-4 days post infection strong IgM 3-4 days post infection strong IgM responseresponse
Trypanosome disappear within hoursTrypanosome disappear within hours
VSG specific IgG appears - not relevantVSG specific IgG appears - not relevant
IgM response often >IgGIgM response often >IgG
After several cycles VSG abs vanishAfter several cycles VSG abs vanish
But abs to invariant ags remain elevatedBut abs to invariant ags remain elevated
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Trypanosome Elimination
Antibody mediatedAntibody mediated
Destruction by Kupffer cellsDestruction by Kupffer cells
Splenic macrophages minor role (cf Splenic macrophages minor role (cf malaria)malaria)
Uptake - C3b - C3bi - direct?Uptake - C3b - C3bi - direct?
C mediated lysis not importantC mediated lysis not important
Trypanosome destroyed within minutes Trypanosome destroyed within minutes
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Immunoregulation
No secondary response to VSG’s unless No secondary response to VSG’s unless cured by chemotherapycured by chemotherapy
Failure of 1ry or 2ndry response prior to Failure of 1ry or 2ndry response prior to deathdeath
Non specific polyclonal activationNon specific polyclonal activation
Suppresser MacrophagesSuppresser Macrophages
Failure of Ag presentationFailure of Ag presentation
Anti idiotype responsesAnti idiotype responses
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Resistance and Virulence
Spectrum of diseaseSpectrum of disease
T. bruceiT. brucei sub species sub species
Host differencesHost differences
Independant of VSGIndependant of VSG
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Vaccination
Effective Antibody responseEffective Antibody response
Phagocytosis & killingPhagocytosis & killing
butbut
Cyclical parasitemiaCyclical parasitemia
Antigenic variation not predicableAntigenic variation not predicable