Immune Evasion Flashcards
It is known that parasite density is required for, but does not always lead to severe malaria. Is there another connection?
In a study in children in Uganda, there was found to be a more diverse antigen repertoire in those w severe malaria
suggesting a correlation between antigenic diversity and disease severity
– no follow up was carried out
How are vaccines being developed to combat antigenic diversity?
blood stage proteins like MSP1 and AMA1 are highly polymorphic
one strategy is to include multiple alleles of a target protein to induce a broader immune response
another is to focus on conserved regions of proteins
– may be poorly immunogenic
How do sporozoites evade complement?
sequestration of C4b via the CSP-C4bBP
– this inhibits the formation of C3 convertase in the lectin and classical pathways
degradation of C3b by plasminogen and factor H
– inhibition of C3 convertase formation in the alternative pathway
How do merozoites evade complement?
Pf92 binds FH which cleaves C3b -> iC3b through Factor-I mediated cleavage
– Pf92 KO shows FH binding reduced and complement damage increased
PfMSP3.1 interacts w C1-INH which interacts w C1q, inhibiting C1 activity
– PfMSP3.1 KO showed decreased C1-INH recruitment and increase in C3b on surface
How does PfEMP1 on RBC surface inhibit complement?
knob restriction inhibits Ab hexamerisation, stopping C1q binding
PfEMP1 shown to bind C1q-binding region of IgM
How do gametes evade complement?
Gap50 binds FH to inactivate C3b, like PF92
How does Plasmodium inhibit DCs?
PfEMP1 binding to CD36
– reduces expression of MHC II and CD86 on their surface
hemozoin can inhibit DC maturation and cytokine production
How does the spleen clear old/damaged/infected RBCs?
blood flows through to sinuses where cells face biochemical challenge from inter-endothelial slits (IES)
unhealthy cells are less deformable so cannot pass through the IES and are take up by red pulp macrophages
During acute malaria, the spleen retains about half of the ring infected RBCs and nearly all schizont infected RBCs
What is pitting?
When an RBC containing an intracellular body (nucleic acid, ferritin, denatured haemoglobin, parasite) tries to cross the IES, body is pulled to the back and physically removed
how the cell doesnt burst is unclear
“Once infected cells” do not live more than a week
– this mimics symptomatic malaria, as RBCs die en masse causing fever
How does malaria interact in those who have been splenectomised?
133 cases of malaria in patients who have had their spleens removed, from 1931 to 2019.
– both severe and acute attacks were more common in these patients
Mature forms of Plasmodium spp. are
found in circulation. Normally, they would be sequestered
– more severe infection is more likely
significant reduction in IgM memory B cells
– patient even more susceptible to reinfection than a healthy patient
How does the spleen restructure in malaria infection?
mouse models
during infection, open circulation turns into a closed system
– forms closed fibroblast barrier associated w fibronectin and collagen
white pulp become disorganised
– causing loss of B cells in marginal zones
– T and B cells scattered due to loss of GCs
How does haematopoiesis change during malaria infection?
increasing demand for myeloid cells, recuing BM capacity to produce erythrocytes and lymphocytes
loss of B cell progenitors during peak parasitaemia is associated w increased B cell development in spleen
– mouse models show the development of atypical B cells
