malaria cycle (hviid, 2004) (marsh et al, 2004). variant surface antigens (vsa) ➲ parasite...

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