Antigenic Variation Flashcards
What is antigenic variation and why do parasites have it?
Look at notes for parasites switching coats diagram
- Parasites can evade your immune response - this is a strategy we see in many parasitic infections
- immune system starts making antibodies that recognise these
- but some of these parasites develop new coats
- red decreases (the things on the surface of the parasite) in number but parasites have switched and are not recognised by the antibodies so now can take over the population
Antigenic variation allows parasites to evade the immune system
Look at notes for diagram
MODEL: antigenic variation is impotent for immune evasion
- body will initially start to get rid of the parasites but not all
- these switch coats and are therefore no longer recognised by the immune system so can continue to attack the rest of the body
- until immune system starts recognising those and so on - waves of parasites
Examples of parasites that use antigenic variation to escape the host immune system
Trypanosoma brucei - sleeping sickness
Plasmodium falciparum - malaria
Giardia - Giaediasis
Trypanosoma brucei - sleeping sickness
- 1000s variant surface glycoproteins - can switch over 1000 times
- DNA recombination and chromatin silencing
- almost infinite repertoire
Plasmodium falciparum - malaria
- Approximately 60 PfEMP1 proteins (but live inside blood cells)
- Chromatin slinging and recombination
Giardia - Giaediasis
- 200 variant surface proteins
- RNAi/siRNA degradation
- Note* - mechanism of antigenic variation in different parasites is not the same
African Trypanosomes
- Trypanosoma brucei rhodesiense (East African Sleeping Sickness)
- Trypanosoma brucei gambiense (West African sleeping sickness)
- Trypanosoma brucei brucei - Nagana in cattle - cannot infect humans
Trypanosoma brucei lifecycle
Check notes for the diagram
- Stumpy form - non proliferation taken up during
Tsetse fly bite i.e. competent for transmission - Tsetse fly (vector) - 10-30 days, midgut to salivary gland
- deliver parasites that can replicate in the blood stream
- Differentiate into form that can be taken up by fly and so lifecycle can continue
Trypanosoma brucei Variant Surface Glycoproteins (VSGs)
- Trypanosoma brucei - sleeping sickness
- Parasite is extra cellular in blood
- 1000s variant surface glycoprotein encoding genes
- Many are incomplete or pseudogenes (these are important despite not per se being functional)
- VSGs homdier (50-60kDa) linked to the parasite plasma membrane via a GPI (glycophosphatydil inositol) anchor
- Approx 5.7 x 10^6 receptors per cell (this is very dense - likely close to maximum density possible)
- VSG coat approx. 12-15nm thick around outside of cell
- Likely protects other plasma membrane proteins from host antibodies
Chromosomes in the T.brucei genome
- 11 megabase sized chromosomes
- 0.9-6Mb in size
- contain all ‘house keeping’ genes and ‘bloodstream expression sites’ and non expressed VSGs - Intermediate sized chromosomes
- It’s are 200-700 kb
- 1 to 7 - number differs between strains
- also contain ‘bloodstream expression sites’ and non expressed VSGs
Blood stream expression sites
Blood stream expression sites are regions where VSG genes are expressed
- blood stream expression sites are at chromosome ends (telomeres) - they all have a similar structure Found in megabase sized and intermediate sized chromosome
- there are only ~ 20 bloodstream expression sites in the genome
- only a single expression is active at any time
- only the VSG (green) encoded within this blood stream expression site is expressed
- All other VSG are transcriptionally silent. This is due to modification of the histones/chromatin such that no transcription occurs
Mechanism 1 - Switching blood stream expression site can switch VSG expression
Check notes for diagram
- there are a limited number of blood stream expression sites - this does not account for all of the diversity of VSG expression
- trypanosome VSGs are expressed from blood stream expression sites but coding sequences are also found elsewhere in the genome
Mechanism 2. Array conversion
Check notes
Mechanism 2. Array conversion - Silent VSG gene (DNA) is copied from a silent VSG array into active expression site
Mechanism 3. Telomeric conversion
- silent VSGs in a silent blood stream expression (check notes for diagram)
Entire telomere replace equivalent sequence in the active blood stream blood stream expression site
Parasite now expressed ‘red’ VSG
Mechanism 4 segmental conversion
Silent VSGs not in bloodstream expression sites (some may be partial genes or pseudo genes)
Parts of several VSG genes are assembled in the active blood stream expression sites to assemble an entirely new VSG (contains parts of multiple VSGs)
Check notes
Key concepts of antigenic variation
- Many parasites express a ‘single’ protein on their cell surface.
- Within the genome there are many gene variants encoding slightly different versions of this particular protein.
- As an immune response recognizes the surface protein parasites expressing a different version will predominate in the population.
- Switching is infrequent and probably stochastic (maybe)?
- It is important to consider the population of parasites (rather than individual parasites) in an infection when thinking about antigenic variation.
- Different parasites use VERY different mechanisms.
