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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
How many species cause malaria? 2 most common
- Plasmodium falciparum
- P. vivax
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
clinical manifestations of malaria (8)
- fever paroxysms: in sync with 48 hour replication in RBCs?
- Nausea, headache, vomiting
- sequestration (P falciparum): cerebral, glomerulonephritis, hypoglycaemia, Blackwater fever (Hb into blood due to RBC bursting - kidney failure), autoimmune haemolysis
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
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)
Where does malarial sequestration take place?
Brain, heart, lung, liver, kidneys, placenta
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
- NO: interferes with neurotransmission
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
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
describe adaptive immune response to malaria
CTLs; antibodies to sperozoites, merozoites, plasmodium proteins on RBCs (eg PfEMP-1)
describe maternal malaria
new target for PfEMP-1 expressed on placenta (CSA - chondroitin sulphate A) that there will not already be immunity for
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
explanation for delay in protective immunity with malaria
infected RBCs bind to DCs and inhibit maturation
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)