Trypanosomiasis Flashcards
What is the causative agent of trypanosomiasis?
Trypanosoma brucei (a kinetoplast)
What is the vector of trypanosomiasis?
Tsetse fly (Glossina spp.), lives in the heart of Africa
Why is trypanosomiasis difficult to immunise against?
Ultimately, all those infected die unless treated, so there is no natural immunity to try to mimic. Additionally, pharmaceutical companies are less prone to engage/invest in drug discovery/development against diseases that affect the poorest people
Describe the selection pressure that drives the immune evasion strategy of African trypanosomes
Since T. brucei is an extra-cellular parasite, it is continuously exposed to cellular and humoral immune system therefore, driving their immune evasion strategy
How does T. brucei evade the immune system?
By using antigenic variation of their variant surface glycoproteins (VSG). VSG molecules are expressed on the cell surface which creates a dense coat that prevents adaptive immunity from detecting or accessing invariant antigens
What is the host’s immune response to T. brucei infection?
B-cell mediated antibody response develops to the parasites’ VSG coat, eliminating most of the parasites from the bloodstream by complement-mediated lysis and opsonisation/phagocytosis.
1% of trypanosomes display an antigenically different VSG, thereby escaping the initial antibody response. Proliferation occurs and a new wave of parasitaemia is observed. Antigenic shift in VSG continues to occur. causing several subsequent waves of parasitaemia (characteristic of HAT)
In what way does antigenic variation succeed?
It prolongs the time that the parasite resides in the host, thereby enhancing transmission to a new host (via tsetse fly). It also allows trypanosomes to infect previously infected hosts
What is a GPI anchor?
A glycolipid that anchors the C-terminus of VSGs to the membrane bilayer
What is meant by antigenic variation?
Describes the existence of several forms of the same gene (var genes) within one organism [same lady, lots o dresses)
What is meant by allelic polymorphism
The existence of genetically stable alternative forms of antigen-coding genes but in different strains
What are both antigenic variation and allelic polymorphism used for?
Both are used to evade the immune system and can be generated by sexual recombination, or mutation and imperfect DNA repair mechanisms
What are VSG genes, and how many of these does the T. brucei genome contain?
A family of genes encoding antigenically distinct surface antigens. T. brucei genome contains 100s, sometimes >1000s of these
What are pseudogenes?
Silent (VSG) genes, organised in tandem arrays
Why must the cell express one variant antigen gene at a time?
To avoid exhausting the surface antigen repertoire
Where are VSG gene arrays located in the chromosome, and what is the significance of this?
VSG gene arrays are located in sub-telomeric regions. Telomeres are particularly recombinogenic areas so this makes them a good place to put genes where diversity needs to be generated (i.e. antigenic variation)
How are the 3 sizes of T. brucei chromosomes referred to?
Megabase, intermediate, and minichromosomes
What does the megabase chromosome code for?
All “house-keeping” genes, expressed in polycistronic (multiple gene containing) transcription units
What are the three mechanisms responsible for the VSG switch?
Duplicative gene conversion (most common in blood stage)
Reciprocal exchange/recombination
Transcriptional control
What is duplicative gene conversion?
Refers to the duplication of a silent gene into the active VSG expression, thereby replacing it.
This is the most important DNA rearrangement mechanism during a chronic infection
How does reciprocal exchange/recombination work?
Involves the exchange of VSG sequences between two chromosomes
How does the transcriptional control mechanism for VSG coat switch work?
A single antigen gene is expressed but periodically that expression is silenced and another gene activated
The most common mechanism in metacyclic (infective) trypanosomes
How can other VSG genes be kept silent?
Pseudogenes - reduces the risk that functional VSG transcripts are produced from gens residing within the VSG arrays
Gene inversion
Boundary elements - may be present at borders between VSG gene arrats and upstream polyscistronic transcription units ensuring efficient termination of RNA pol II (prevents transcription)
Physical separation from expression site body (VSG expression is restricted to the expression site body)
