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How many people at risk from malaria? How many clinical cases per year?
2 billion at risk, 300 million clinical cases per year
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How many species cause malaria? 2 most common
- 5
- Plasmodium falciparum
- P. vivax
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Describe life cycle of plasmodium
- Sporozoities into blood stream after bite from infected mosquito
- Sporozoites infect hepatic cells (may become latent hypnozoite)
- Mature schizont releases merozoites
- Merozoites infect RBCs: 48 cycle of replication
- Gametocytes in blood taken up by mosquitoes
- microgamete becomes macrogamete become zygote become motile ookinete
- Ookinete embeds itself in mosquito midgut and becomes oocyst
- Oocysts burst to release sporozoites into salivary gland of mosquitoe
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clinical manifestations of malaria (8)
- fever paroxysms: in sync with 48 hour replication in RBCs?
- Nausea, headache, vomiting
- splenomegaly
- sequestration (P falciparum): cerebral, glomerulonephritis, hypoglycaemia, Blackwater fever (Hb into blood due to RBC bursting - kidney failure), autoimmune haemolysis
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Which is the most dangerous species that causes malaria? Why?
- P. falciparum: causes sequestraion, especially cerebral sequestration
- Upregulation of cell adhesion molecules, meaning RBCs bind to endothelial cells in brain, heart, lung, liver, kidneys, placenta
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What proteins/genes are involved in malarial sequestration?
- RBCs express PfEMP-1 (from 1 of 50 var genes)
- Binds to endothelial cell proteins: CD36, ICAM-1, VCAM-1, CSA (chondroitin sulphate A)
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Where does malarial sequestration take place?
Brain, heart, lung, liver, kidneys, placenta
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Involvement of cytokines in cerebral malaria
- RBC rupture releases malarial toxins eg GPI (glycosyl phosphotidyl inositol) which is recognised by TLRs on macrophages (also acts as a membrane anchor for several merozoite membrane proteins)
- TNF-alpha: increased NO; increased ICAM-1 expression: increased adhesion
- IL-1
- NO: interferes with neurotransmission
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4 blood changes that are protective against malaria?
- Duffy blood group antigens against P vivax
- Sickle-cell anaemia: parasite dies due to intracellular changes on deoxygenation
- Other thalassaemias (abnormal alpha or beta chain of Hb)
- Glucose-6-phosphate dehydrogenase deficiency: may affect parasite growth or promote efficient phagocytosis of infected RBCs
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Describe relationship between sickle-cell anaemia and malaria
- Sickle-cell anaemia: valine substituted for glutamic acid in beta-chain of haemoglobin
- HbS deoxygenation: RBC distorts and looses potassium: death of parasite
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describe adaptive immune response to malaria
CTLs; antibodies to sperozoites, merozoites, plasmodium proteins on RBCs (eg PfEMP-1)
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describe maternal malaria
new target for PfEMP-1 expressed on placenta (CSA - chondroitin sulphate A) that there will not already be immunity for
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describe antigenic variation in malaria
- 50 var genes for PfEMP1: avoid anti-malarial immunity and avoid destruction of parasitised RBCs by sequestration in spleen
- other highly polymorphic proteins on infected RBCs eg rif
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explanation for delay in protective immunity with malaria
infected RBCs bind to DCs and inhibit maturation
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mechanisms for control of malaria (4 broad areas)
- reduction of human-vector contact (mosquitoe repellants, bed nets, house spraying)
- breeding habitats (drainage, insecticides, larvicides)
- transgenic mosquitoes (creating ones resistant to malaria)
- drugs (prophylactic for travellers, vaccines - none yet)
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