African trypanosomiasis Flashcards
What is sleeping sickness? Describe its vector and epidemiology.
Also known as African trypanosomiasis, it is a fatal disease caused by Trypanosoma brucei spp and it is carried by the tsetse fly.
The trypanosome brucei is an extracellular parasite unlike T.cruzi.
It’s endemic in certain areas of sub-Saharan Africa, most predominantly the ‘tsetse belt’ in low western Africa.
What are the three subtypes of T. brucei?
- Trypanosoma brucei gambiense –
- - humans are main reservoir (but also found in pigs)
- - can take years for symptoms to develop - causes a chronic condition.
- - Found in central and western Africa. - Trypanosoma brucei rhodesiense –
- - game cattle are main reservoir, takes several months to develop.
- - Causes acute condition that rapidly progresses to death. – Found in eastern and southern Africa. - Trypanosoma brucei brucei –
- - not infective to humans, causes African animal trypanosomiasis called Nagana – characterised by fever, weakness and is fatal if left untreated.
How is Rhinderpest linked to sleeping sickness?
the once epidemic disease destroyed wildlife, wiping out buffalo, giraffe and antelope in parts of eastern Africa.
- This made the environment ideal for the tsetse fly as before grazing had kept the grassland from growing into dense fields and thickets.
- Epidemic of sleeping sickness followed in Uganda in 1902-6. Nagana and sleeping sickness further decreased cattle and human populations, which led to even better habitats for tsetse fly
(rhinderpest is now eradicated)
Describe the life cycle of T.brucei
(The entire life cycle of African Trypanosomes is represented by extracellular stages)
– During a blood meal on the mammalian host, an infected tsetse fly (genus Glossina) injects metacyclic trypomastigotes into skin tissue.
In the human
- The parasites enter the lymphatic system and pass into the bloodstream.
- Here they transform into bloodstream trypomastigotes, are carried to other sites throughout the body and rapidly replicate by binary fission
- The tsetse fly becomes infected with bloodstream trypomastigotes when taking a blood meal on an infected mammalian host.
In the fly
- In the fly’s midgut, the trypomastigotes transform into procyclic trypomastigotes, which involves changes in surface proteins (loss of VSG) and metabolism.
- They then multiply by binary fission, leave the midgut, and transform into epimastigotes in the salivary glands.
- The epimastigotes will adhere to epithelia via their flagellum and continue multiplication by binary fission until they mature into metacyclic trypomastigotes
– The cycle in the fly takes approximately 3 weeks.
Describe the stages and symptoms of sleeping sickness
Early stage - fever, headache, joint pain. Sometimes a localised nodule called a trypanosome chancre is seen. Once it passes the BBB, the parasite can cause permanent brain damage.
Later stage (in the CNS) – constant headache, loss of appetite, wasting, skin is too soft. Sleep cycle is disturbed greatly, speech disorders, hallucination and behavioural changes.
Final stage – coma and death.
Describe the strategies of success for T.brucei
Crossing the blood brain barrier
- The parasite will cross the BBB at post-capillary venules through a process similar to lymphocytes.
- Blood-brain barrier separates cerebrospinal fluid from bloodstream: composed of epithelial tissue, with tight junctions between epithelial cells.
- T. brucei infections will cause inflammation that will weaken the BBB and cause release of cytokines that will lead to accumulation of parasite in the CSF.
- The parasite can then alter neuronal function: by psychiatric, motor, sensory and sleep disturbances.
- The most notable feature is sleep alterations: characterised by extreme fatigue in the day and agitation at night.
- The pro-inflammatory cytokines (released when trypanosomes secrete prostaglandins) are thought to affect the brain areas involved in sleep-wakefulness regulation including the suprachiasmatic nucleus, to cause these changes.
- The face also becomes edematous with a blank expression.
- If left untreated, the disease will progress to include convulsions and coma followed by death.
Antigenic variation
- To establish a long-term chronic infection, the trypanosome must find ways to avoid the immune system. E.g. the trypomastigote has a thick surface coat which prevents complement-mediated lysis.
- However eventually antibodies will be made against surface proteins they reside extracellularly, leading to antibody-mediated lysis of most parasites.
- A number, however, will change their antigenic properties every time they undergo sexual reproduction so that they can avoid this.
- These will rapidly increase in number as they are not recognised by antibodies. Eventually an Ab will be developed leading to another fall.
- This results in cyclical peaks of parasitemia in which each peak is a new antigen population.
- A different variant of the surface glycoprotein (variant surface glycoprotein - VSG) on their coat is encoded by a few cells each generation. These won’t be recognised by most antibodies, and they will proliferate until the next cycle where they will carry out the same process.
- The fact that multiple genes code for VSGs with different N-terminal domains makes vaccine development difficult.
- However there isn’t high variability of VSG in tsetse fly, so possible solution is to produce an ‘altruistic’ vaccine that would kill tsetse fly forms of the parasite. The antibody would be taken up by fly in its meal so that it can’t infect anyone else later on. The first person however won’t be protected.
What are the treatment options for sleeping sickness?
Pentamidine –> recommended for stage 1 of disease, however it has several side effects including pancreatitis.
Suramin –> also used for stage 1, side effects include nausea, vomiting and risk of adrenal cortical damage.
Melarsoprol (arsenic in antifreeze) –> Only drug available in most of tsetse belt for stage 2.
- Fatal to about 10% of users.
- A total of nine slow, very painful injections.
- Allergic reaction can occur: fatal swelling of brain. If patients survive this: irreparable nerve damage
Eflornithine –> Produced by pharmaceutical company Aventis in the 1990’s but not profitable so production discontinued.
- – Luckily same active ingredient as Vaniqa, a product used to stop the growth of excessive facial hair in women, so a deal reached between Aventis and WHO; from 2001 supplied free.
- Can penetrate blood-brain barrier. Much safer than melarsoprol (!) but still has many side effects and can be fatal. Four 2-hour long i.v. injections for 14 days, so can only be used in well-staffed health centers
What are the methods of vector control for the tsetse fly?
The tsetse fly is easier to control than the mosquito as it is larger and it flies more slowly.
– Tsetse fly is unusual as it uses proline and alanine to generate ATP for flight and they can only sustain this metabolic output for short periods (flights < 1 km).
Methods:
- Traps - Flies attracted to blue or black trap, then move upwards towards the light, where they are trapped. Traps made more effective by adding odours (acetone, pheromone …)
- Baits/insecticides – the traps can also be treated with insecticides.
- Control reservoir hosts – e.g. game cattle.
- Clear vegetation to provide barrier – this involves destruction of tsetse habitats such as clearing stream banks of trees and shrubs.
- Release of sterile males (sterile insect technique)
Describe the sterile insect technique method.
- this approach abolished tsetse fly in zanzibar.
Method
- Rear flies in lab.
- Sterilize males with gamma radiation.
- Release a very large number of males.
- These will fertilize a large number of females, which will then not lay eggs, so that the population decreases
–> To ensure that SIT is successful you have to make the ratio of sterile males to fertile males to 10:1 to guarantee that every female will mate with a sterile male. (8 mil were released in Zanzibar.)
This method also eradicated the screw worm in the USA.
What are the challenges of the sterile insect technique?
It has failed before –> such as in control of the Aedes aegypti which is vector of yellow fever and dengue.
- 850 sterile males were released every week in Mombasa, but while the larvae in breeding sites dropping dramatically the number of adult females was not affected.T
- this was due to the Aedes not migrating and only staying in small villages it was released. Also the Aedes mate several times, so more should have been released.
Success of the SIT depends on mating frequency, scale of release (number and area) and the density dependence at appropriate stage in life cycle.
–> can SIT work on a large scale for the tsetse fly?
For: females only mate once, no density dependence at larval stage.
Against: However large areas must be covered to inhibit immigration and over 20 species exist in Africa.
