Human African Trypanosomiasis - 1b Flashcards Preview

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1

Human African Trypanosomiasis 

is also known as

African Sleeping Sickness

2

Human African Trypanosomiasis 

prevalence

  • 36 countries in sub-Saharan Africa
  • 60 million people at risk
  • common in rural populations
  • prevalence in villages in Angola, the Democratic Republic of Congo, and Southern Sudan is between 20% and 50%
  • associated wit hpoverty
  • zoonotic (domstic and wild animals) and anthropomorphic transmission cycles

 

3

Human African Trypanosomiasis 

epidemics

  • 1896-1906
  • 1920-1940
  • late 1970s - 2000
  • 3 main epidemics correlate with monitoring for disease
    • stop screening → number of reported cases increased
  • screening by NGOs
    • too dangerous in war/unrest → stop screening and testing

 

 

 

 

4

Transmission

  • T. brucei transmitted in saliva of tsetse fly (Glossina spp)
  • male and femal flies transmit disease
  • very painful bite
  • 34 different species and sub-species

 

5

Tsetse fly split into 3 groups based on 

  • distribution
  • behaviour
  • molecular 
  • morphology

 

  • riverine flies - associated with water
  • savannah - associated with open land
  • forest

 

  • different groups have different abilities to tranmit different HAT forms

 

6

Female flies are

viviparous

  • deposits a fully developd larva
  • burrows into the soil
  • pupates
  • emerges as an adult fly (month later)
  • newly-hatched flies not infected with trypanosomes
    • picks up trypanosome from animal or human host, not born with it

 

multivoltine

  • typically producing 4 generations per year
  • up to 31 generations over lifespan

 

7

Female flies are key to

vector control

8

Distribution of HAT and Tsetse fly

wherever you have the tsetse fly you have the disease

9

HAT is caused by the protozoan parasite

Trypanosoma brucei

 

10

Major forms of the parasite

(T. brucei)

  • 2 mastigote forms but one has 4 variants
  • trypomastigote
    • procyclic trypomastigote
    • bloodstream trypomastigote
    • metacyclic trypomastigote
    • short stumpy trypomastigote
  • epimastigote

 

11

Major form of T. brucei

trypomastigote (general)

  • common morphology in mammalian and insect hosts
  • common morphology of infective forms

 

  • the form of the parasite that lives within our blood stream and our lymphatic system 
  • also the form of the parasite that lives within the gut of the insect vector
  • form of the parasite that's transmitted from the insect to us and from us back to the insect

(4 forms - one in us, one in insect, 2 transmissable forms)

 

12

T. brucei

procyclic trypomastigote

 

INSECT​

  • divide by binary fission
  • cell coat - procyclin
  • lives in midgut of the tsetse fly

 

 

13

T. brucei

bloodstream trypomastigote

 

mammal

  • found in humans and ungulate animals
  • long, slender, bloostream trypomastigote
  • divide by binary fission
  • cell coat of variant surface glycoproten (VSG) to evade antibody-mediated immune destruction
  • lives in bloodstream (or lymphatic system) - extracellular parasite, kicks RBC out of the way

 

14

T. brucei

metacyclic trypomastigote

insect → humans

  • unable to divide
    • infectious forms compared to replicative forms is that these infectious forms are pre-adapted for life in the forthcoming host (adapted for life in human)

  • spat out in the saliva of the tsetse fly
  • the form that infects us

 

15

T. brucei

short stumpy trypomastigote

human → insect​

  • unable to divide
    • infectious forms compared to replicative forms is that these infectious forms are pre-adapted for life in the forthcoming host (adapted for life in insect)
  • form that we infect the tsetse fly

 

16

T. brucei

epimastigote 

  • common morpholog in insect salivary gland

 

17

Trypomastigote 

(picture)

A image thumb
18

Epimastigote

(picture)

A image thumb
19

Life cycle of T. brucei

(overall picture)

A image thumb
20

Q image thumb

  • as tsetse fly takes a blood meal, parasites (metacyclic trypomastigotes) injected from salivary gland into victims bloodstream (salivarian)
  • injects saliva into host containing anti-coagulants etc
  • also injects the metacyclic trypomastigote - if the fly is infected - into blood or lymphatic system of host

 

 

21

As tsetse fly takes a blood meal, parasites 

(metacyclic trypomastigotes) injected from salivary gland into victims bloodstream (salivarian)

  • injects saliva into host containing anti-coagulants etc
  • also injects the metacyclic trypomastigote - if the fly is infected - into blood or lymphatic system of host

 

22

Q image thumb

  • injected metacyclic trypomastigotes transform into bloostream form (BSF) trypomastigotes 
  • long-slender bloodstream form
  • trigger = temperature? (unknown)
  • BSF trypomastigotes multiply by binary fission in various body fluids (blood, lymph, spinal fluid)
    • begin dividing and colonizing bodily fluids
    • initally in blood and lymphatic system, but if given enough time, will cross the blood-brain barrier to get into the cererbal-spinal fluid
  • in the human host the long-slender BSF trypomastigotes appear to be able to sense the number of other parasites around them, and through a core sensing mechanism they can talk to each other, get a rough idea of the numbers of parasites, and if the population gets too high they express stumpy induction factor

 

23

Injected metacyclic trypomastigotes transform into 

bloostream form (BSF) trypomastigotes 

  • long-slender bloodstream form
  • trigger = temperature? (unknown)
  • BSF trypomastigotes multiply by binary fission in various body fluids (blood, lymph, spinal fluid)
  • begin dividing and colonizing bodily fluids
  • initally in blood and lymphatic system, but if given enough time, will cross the blood-brain barrier to get into the cererbal-spinal fluid
  • in the human host the long-slender BSF trypomastigotes appear to be able to sense the number of other parasites around them, and through a core sensing mechanism they can talk to each other, get a rough idea of the numbers of parasites, and if the population gets too high they express stumpy induction factor

24

Q image thumb

  • BSF trypomastigotes differentiate into short stumpy (SS) trypomastigotes 
    • trigger unknown - stumpy induction factor
    • in the human host the long-slender BSF trypomastigotes appear to be able to sense the number of other parasites around them, and through a core sensing mechanism they can talk to each other, get a rough idea of the numbers of parasites, and if the population gets too high they express stumpy induction factor
    • stumpy induction factor causes the long slender BSF parasite to shrink and form the short-stumpy trypomastigote
    • stumpy induction factor produced in a density-dependent manner
  • SS trypomastigotes can't divide 
    • pre-adapted for life in insect
  • tsetse fly takes a blood meal and ingests BSF and SS trypomastigotes
    • they pass into the gut of the insect
    • if the SS form isn't taken up, human immune system will kick in and wipe it out
    • dead-end unless the SS gets into the tsetse form
  •  

25

BSF trypomastigotes differentiate into 

short stumpy (SS) trypomastigotes 

  • trigger unknown - stumpy induction factor
    • in the human host the long-slender BSF trypomastigotes appear to be able to sense the number of other parasites around them, and through a core sensing mechanism they can talk to each other, get a rough idea of the numbers of parasites, and if the population gets too high they express stumpy induction factor
    • stumpy induction factor causes the long slender BSF parasite to shrink and form the short-stumpy trypomastigote
    • stumpy induction factor produced in a density-dependent manner
  • SS trypomastigotes can't divide 
    • pre-adapted for life in insect
  • tsetse fly takes a blood meal and ingests BSF and SS trypomastigotes
    • they pass into the gut of the insect
    • if the SS form isn't taken up, human immune system will kick in and wipe it out
    • dead-end unless the SS gets into the tsetse form

 

26

Q image thumb

  • in tsetse fly midgut, BSF trypomastigotes die
  • SS trypomastigotes transform into procyclic trypomastigotes 
    • SS form survives, go into the midgut of the insect vector where they respond to...
    • trigger - temperature/citrate/cis-aconitate (temp and carbs)
  • procyclic trypomastigotes multiply by binary fission
  • colonize insect gut

 

27

in tsetse fly midgut, BSF trypomastigotes die


SS trypomastigotes transform into 

procyclic trypomastigotes 

  • SS form survives, go into the midgut of the insect vector where they respond to...
    • trigger - temperature/citrate/cis-aconitate (temp and carbs)
  • procyclic trypomastigotes multiply by binary fission
  • colonize insect gut

28

Q image thumb

  • procyclic trypomastigotes leave themidgut
    • can either get back up through the digestive system and can get back into the salivary gland 
    • or the procyclic form somehow can access the hemocyl (insect blood supply) to get into the salivary gland
  • migrate to the salivary gland
  • procyclic trypomastigotes transform into epimastigotes
    • trigger unknown

29

procyclic trypomastigotes leave themidgut and goes to the

 

salivary gland

  • can either get back up through the digestive system and can get back into the salivary gland 
  • or the procyclic form somehow can access the hemocyl (insect blood supply) to get into the salivary gland
  • procyclic trypomastigotes transform into epimastigotes
  • trigger unknown

 

30

Q image thumb

epimastigotes in the salivary gland:

  1. attach to epithelial cells via flagella
  2. divide by binary fission
  3. sexual reproduction can occur (genetic exchange is NOT an essential stage in life cycle, doesn't involve meiosis - 2 diploid organisms fuse to form a tetraploid, with time lose genetic information to go back toward a diploid state) to colonize that organ
  4. transform into metacyclic trypomastigotes (trigger unknown)
  • some epimastigotes undergo a cell division that will result in one epimastigote and one metacyclic trypomastigote
  • probably density dependent
  • the epithelial cells have changed, and parasite off of epithelial cells into lumen (metacyclic form) that's ready to be spat out into the next mammalian host

 

31

2 sub species of T. brucei cause HAT

  • Trypanosoma brucei gambiense
    • West African trypanosomiasis

 

  • Trypanosoma brucei rhodesiense
    • East African trypanosomiasis

 

  • differences between the 2 forms

 

32

Trypanosoma brucei gambiense

West African trypanosomiasis

33

Trypanosoma brucei rhodesiense

East African trypanosomiasis

 

34

Other African trypanosomiasis

  • found predominantly in ungulate mammals
  • sub of brucei
  • Trypanosoma brucei brucei
    • not infectious to humans
    • restricted to cattle
  • Trypanosoma vivax
  • Trypanosoma congolense
    • above 2 can resist human complement but this form is susceptible to our human complement

 

 

35

East African trypanosomiasis

tsetse fly

savannah

36

West African trypanosomiasis

tsetse fly

riverine

37

East African trypanosomiasis

ecology

dry bush/woodland

38

West African trypanosomiasis

ecology

rainforest

rivers

lakes

39

East African trypanosomiasis

geographical range

East/Southern Africa

40

West African trypanosomiasis

geographical range

West/Central Africa

41

Meeting of East and West forms

  • East and West forms meet in Uganda
  • because of cattle movement worry that the forms will be brougth into contact
  • worry that in salivary gland of the insect vector epimastigotes can have sex
    • what if the 2 forms get on?
    • may get genetic mixing, what will it produce?
    • over time, as a result of cattle migration the 2 parasite forms are getting closer

 

42

East African trypanosomiasis

transmission cycle

zootic

ungulate → human

involving animals

 

(animal - human - animal)

43

West African trypanosomiasis

transmission cycle

anthropomorphic

human → human

 

44

East African trypanosomiasis

non-human reservoirs

wild and domestic animals

45

West African trypanosomiasis

non-human reservoirs

rare

46

East African trypanosomiasis

epidemiology

sporadic, safaris

47

West African trypanosomiasis

endemic, some epidemics

48

East African trypanosomiasis

disease progression

rapid progression to death

49

West African trypanosomiasis

disease progression

slow progression (~1 year) leading to death

50

East African trypanosomiasis

parasitaemia

high

51

West African trypanosomiasis

parasitaemia

low

52

East African trypanosomiasis

asymptomatic carriers

rare

53

West African trypanosomiasis

asymptomatic carriers

common

(always there at a very low level)

(difficult to detect in the first place by looking at a blood smear)

54

In the west

  • low level constantly going on
  • number of asymptomatic cases
  • undersestimate number of cases because it's there in a lot of people but at a very low level
  • not getting treated because not ill, even though it's there
  • asymptomatic to life-threatening can take a long time (long-lasting chronic infection)

 

55

In the east

  • nothing - nothing - spikes
  • sporadic outbreaks
  • like wildfire - affect a lot of people then die back very quickly
  • parasite burden is very high
    • humans find it very difficult to suppress parasite numbers
  • low number of asymptomatic cases
    • because if you get this form of the disease you transfer from asymptomatic to symptomatic very quickly (acute infection)
    • infection to death as little as 3-4 weeks

 

56

Pathology

early stage

blood1

blood

  • chancre arises at site of bite in 50%
    •  moreso with T. b. rhodesiense infections
      • probably more due to the tsetse fly than the infection
  • can heal leaving altered pigmentation 
    • diagnostic, particularly of rhodesiense form

 

57

Pathology

early stage

blood2

  • long slender form begins to divide and colonizes the blood
  • intermittent fever, headache
    • fibrile episodes of feeling hot then cooled down, again by the week
    • because immune system trying to wipe the parasite out
    • body responding to antigen insults being thrown at immune system

58

Pathology

early stage

lymphatics

  • spreads to body and starts to invade other fluids - including lymphatic system
  • continued fibrile episodes
  • lymphadenopathy
    • localized edemas - water collection
    • swelling of the lymph glands
    • eg Winterbottom's sign - enlarged neck gland
  • deteriorating health

59

Pathology

late stage

CNS

  • severe sleep disturbance

can still get treated and recover, but if not:

  • severe neurological symptoms
  • convulsions
  • coma
  • personality change
  • death

arsenic treatment in East form, but arsenic is lethal also

60

Comparing pathology

A image thumb
61

Diagnosis

  • must be cheap, can't rely on power supply
  • direct methods
    • blood smear
    • enrichment
      • DEAE anion exchange
      • microhaematocrit
    • cerebrospinal fluid

 

62

Diagnosis

direct

blood smear

  • ok for East form where parasitaemia can get very high
  • not good for West form where parasite density doesn't get very high

 

63

Diagnosis 

direct

enrichment

enrichment

  • DEAE anion exchange column
    • RBC stay in column, parasites pass through
    • can use concentration methods - use ion exhchange column to bind out red blood cells and allow parasites to come through
  • microhaematocrit (buffy coat)
    • capillary tubes sealed at one end, suck blood up and put into specialized centrifuge, spin to package out all components of blood 
    • RBC at bottom - WBC with buffy coat - plasma on top
    • look at buffy coat for presence or parasite

 

64

Diagnosis

direct

cerebrospinal fluid

lumbar punctures to diagnose people with late stage symptoms

65

Diagnosis

indirect (seriology)

CATT

 

Card Agglutination Test for Trypanosomiasis

 

drop of blood

+  fixed (dead) parasites on a plastic card

⇒ blue granular deposits = infection

 

  • looking for antibodies against the parasite in the person's blood
  • if you have antibodies against the parasite it will agglutinate the parasites together to form a granular deposit
  • not infected = no blue granulation
  • only works for T. b. gambiense BUT is cheap (25cents/test)
    • need diagnostic tests for East form that kills you faster

 

66

5 licensed drugs

  1. Suramin
  2. Pentamidine
  3. Melarsoprol
  4. Eflornithine
  5. NECT (nifurtimox-eflornithine combinational therapy)

 

67

Prevention and control

  1. pre-20th century
  2. land clearing
  3. slaughter of wild animals
  4. pesticide campaigns
  5. trapping
  6. irradiated males

 

  • control efforts undertaken throughout the African continent long-term sustainable control rarely achieved
  • tsetse control efforts tied to poverty, health, politics

 

68

Prevention and control

pre-20th century

humans didn't settle or cultivate crops in areas where fly prevalent

69

Prevention and control

land clearing

 

  • removal of brush and woody vegetation from area
  • Tsetse tend to rest on trunks of trees
    • hop around rather than flying

 

if remove the threat, humans will move into the savannah

 

70

Prevention and control

slaughter of

wild animals

71

Prevention and control

pesticide campaigns

  • aerosol sprays (DDT)
    • ecosystems rebelled against
  • pour on formulations (cattle)

 

72

Prevention and control

trapping

  • can trap the flies
  • attracted to dark objects
  • put insecticide in dark object

 

73

Prevention and control

irradiated males

 

  • try to breed out the disease

 

74