Malaria Cycle

1
Malaria Cycle
(Hviid, 2004)

• (Marsh et al, 2004)

2
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.

3
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)
4
Research questions

• Why is VSA_SM antigenically conserved?
• Why does every parasite contain VSA_SM?

5
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)

6
Between-host dynamics

• Vector transmission
• High transmissibility
• High diversity
• Multiple infections during lifetime (SIS)

7
Model
VSAs 1, 2, 3, 4, ... Parasites 1,2, 1,3,
2,3, ... Stronger VSA 1 gt 2 gt 3 gt 4 gt ...

• 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

Within-host
Between-host
8
Flow diagram
9
Results (2 loci)

• 5 VSA, 2 loci

10
Results (2 loci)
11
Results (1 locus)

• 5 VSA, 1 locus

12
Frequency VSA_SM (VSA 1)

• Variable VSA, 2 loci

13
Results (superinfection and scaled mu)

• 5 vsa, 2 loci, superinfection, high birth/death
  rate

14
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

15
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