sleeping sickness presentation
TRANSCRIPT
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Enter Sandman…
“The in vivo dynamics of antigenicvariation in Trypanosoma brucei”Monica R. Mugnier, George A. M. Cross, F. Nina Papavasiliou. Science 347: 6229, 2105. 1470-3
Joshua Gefen
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Sleeping Sickness[African Trypanosomiasis]
• A disease caused by a parasitic flagellate protozoa of the species Trypanosoma brucei
• Infects both humans and animals (Nagana disease)
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• The transmission of the Trypanosoma brucei between mammal hosts is usually by insect vector – the Tsetse fly
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Disease Agent• Life cycle
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Genome and Genetics• 11 pairs of large chromosomes of 1 to 6
megabase.• 3 to 5 intermediate chromosomes of 200-
500 kilobase.• Around 100 mini-chromosomes of 50-100
kilobase. These may be presented as multiple copies per haploid genome.
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VSG Coating[Variable Surface Glycoprotein]
• A conserved C-terminal domain
• A variant and highly changeable N-terminal domain
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VSG Characteristics• Trypanosoma brucei populations can peak at a size of 1011
within a host, while ‘switching’ frequency is 0.1% per division
• The switching of VSG can be identified as a stochastic system – having a random probability distribution or pattern.
• This rapid rate of switching is the basis of the constantly diverse VSG population and the evasion of the protozoa from detection by the immune system.• The clinical effect of this cycle is a successive wave of
parasitaemia.
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VSG Expression
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Trying to understand the pattern or the hierarchy of VSG population as they expressed in a host.
And now for the article…
“Despite attempts of modelling little is known about the kinetic of VSG expression during infection.”
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Methods
• Control Libraries.
• Infection and Sample Collection
• VSG-Seq library
• Mosaic and identification
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Figure 1: VSG-seq for assembly and quantification of VSG
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Figure 2: Complex Dynamics of VSG Expression
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Figure 3: Variant VSG Emergence During Infection (Minor vs. Major)
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Minor Problem
[Total population: 192]
“Although each infection initiated with a different major VSG, the majority of variants (86%) appeared in more than one infection, and nearly half (46%) appeared in all four infections (Fig. 3C).” p. 1472
“Of the 48 VSGs that appeared in all four infections, few were consistently dominant, and few were only ever expressed as a minor variant (Fig. 3B).” p. 1472
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Figure 4: Mosaic VSGs
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Conclusion• In their experiment, all the VSGs observed (65-
135 before day 30), may represent up to 35% of the pre-existing repertoire. These represent a lower-than-expected VSG expressed diversity.
• The results show that VSG switching does not occur at the “expected” rate – not enough for immune evasion.
• Contrary to that, in-field observations and samples indicated a higher-than expected VSG diversity.
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Thank you…