malaria cycle (hviid, 2004) (marsh et al, 2004). variant surface antigens (vsa) ➲ parasite...
Post on 22-Dec-2015
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Malaria Cycle
(Hviid, 2004)
(Marsh et al, 2004)
Variant Surface Antigens (VSA)
➲ Parasite proteins expressed by iRBCs.➲ Each parasite has a repertoire of ~60 var
genes for PfEMP1, where each iRBC expresses one type.
➲ PfEMP1 regulates the adhesion properties.
➲ Major target for the adaptive immune system.
VSA_SM (Severe Malaria)
➲ An antigenically conserved group, in time and space, associated with severe disease.
➲ Positively selected in naive hosts.➲ Each parasite seems to contain VSA_SM.
(Bull et al, 2000)
Research questions
Why is VSA_SM antigenically conserved?
Why does every parasite contain VSA_SM?
Within-host dynamics
➲ After release of the merozoites by the liver, the whole repertoire of VSAs are expressed.
➲ In a few days, all the iRBCs tend to express the same VSA.
➲ During infection, the iRBCs can clonally switch to express a different VSA (switching matrix)
Between-host dynamics
➲ Vector transmission➲ High transmissibility➲ High diversity➲ Multiple infections during lifetime (SIS)
Model
➲Upon infection by a parasite, the strongest VSA for which there is no immunity will be expressed➲After clearance, the host has build up immunity against the expressed VSA
➲SIR-model with homogeneous mixing➲Equilibrium analysis
VSAs: 1, 2, 3, 4, ...Parasites: {1,2}, {1,3}, {2,3}, ...Stronger VSA: 1 > 2 > 3 > 4 > ...
Within-host
Between-host
Flow diagram
Results (2 loci)
5 VSA, 2 loci
Results (2 loci)
Results (1 locus)
5 VSA, 1 locus
Frequency VSA_SM (VSA 1)
Variable # VSA, 2 loci
Results (superinfection and scaled mu)
5 vsa, 2 loci, superinfection, high birth/death rate
Extensions
➲ Superinfection.➲ VSA dependent disease dynamics.➲ Cross-immunty between the VSAs.➲ Immunity based on number of infections.➲ Recombination in the parasite.➲ VSA_UM without adaptive immunity
Conclusions
➲ (Very much work in progress)➲ In the basic model, it cannot be explained
why each parasite should contain some VSA_SM. The conservedness could be explained by its lower prevalence.
➲ Extensions could show that each parasite contains some VSA_SM, but its conservedness is harder to explain.
➲ Epidemiological data on VSA expression is needed