Parasitology lecture 2 Flashcards
Malaria
malaria - cases, deaths, agent
1 - at least 300million cases a year, 1million deaths a year in africa alone
2 - caused by intracellular protozoa of genus plasmodium
3 - four species cause malaria in humans, the 2 most common are P.falciparum and P.vivax
malaria life cycle? from infection of mosquito.
male/female gametocyte taken up in blood - microgamete - macrogamete - zygote - ookinete - migrate across mosquito midgut - oocyst - cyst bursts to release sporozoites which enter the salivary gland and are injected in to next host during feeding - migrate to liver to enter hepatic cells - if dormant its called a hypnozoite if it they mature the cell is termed a mature liver schizont - ruptures to release merozoites which enter blood stream to infect erythrocytes - tropnozoite - erythrocytic schizont - reptures erythrocyte to release male and female gametocytes. - repeat.
what are the clinical manifestations of malaria?
1 - paroxysmal fever (differs between vivax and falciparum).
2 - headache, nausea
3 - anaemia, splenomegaly, sequestration of parasitized RBCs in the brain and other organs (only falciparum)
4 - hypoglycaemia and other metabolic disorders
5 - glomerulonephritis/tubular necrosis
6 - blackwater fever, autoimmune haemolysis.
7 - falciparum is multisystem, the most dangerous type causing severe malaria inc cerebral malaria. 15-20% of children infected will die, even with treatment.
overview of which species causes sequestration, how and where?
1 - only P.falciparum, causes infected RBCs to express proteins on surface causing adhesion to endothelial cells
2 - occurs in multiple organs inc brain, heart, lung, liver, kidneys and placenta.
3 - sequestration in brain thought to be central to cerebral malaria development
what is cerebral malaria?
1 - caused by P.falciparum only.
2 - sequestration in cerebral capillaries and venules.
3 - specific set of clinical symptoms inc convulsion, impaired consciousness and most severely an unrousable coma.
how does malaria cause sequestration of RBCs and the outcome.
1 - prevents clearance of infected erythrocytes by the spleen causing c high parasitaemia
2 - involves - modifies RBCs to express parasite protein PfEMP-1 = knob-like projections
3 - interacts with endothelial cells - CD36, ICAM-1, VCAM-1, CSA (chondroitin sulphate A)
4 - PfEMP-1 encoded by large and diverse gene family called var genes. different variants of the protein binds many receptors.
5 - only P.falciparum sequesters and only one to cause cerebral malaria indicating that the process is central to the manifestation.
6 - cerebral malaria pathogenesis not entirely understood, multiple possible mechs.
possible mechanism of cerebral malaria?
1 - block cerebral blood vessels, tissue hypoxia and inadequate nutrients causing local necrosis. possible objection as early work suggests that specific malaria treatment is followed by a full recovery in a high proportion of patients so other mechs sought. more recent work shows around 25% of children have long term impairment esp in cognition, motor, behaviour and epilepsy. considered a leading cause of neuro-disability in african children. less apparent in adults.
role of cytokines in cerebral malaria?
1 - cyto and chemokines play complex roles, both protective and damaging.
2 - TNFalpha, IL-1 and NO production may contribute to symptoms.
3 - parasite antigen/toxins released on RBC rupture trigger production of pro and anti-inflammatory cytokines
4 - one toxin is glycosylphosphotidyl inositol (GPI) which functions as a membrane anchor for several merozoite membrane proteins.
5 - GPI stimulates TNF prod, which may upreg ICAM-1 - adhesion
6 - TNF may also upreg NO expression, may cross BBB and interfere with neural transmission.
7 - TNF also involved in synaptic transmission regulation (strength, scaling and LTP)
How may the BBB be disrupted in cerebral malaria?
1 - sequestration initiates - inflam cytokine transcription - changes in cell signal transduction - endothelial activation - apopotosis of endothelium - BBB breakdown 2 - causing - intracranial hypertension, cerebral oedema, cerebral artery compression, ischaemia, and death 3 - also an inflammatory response initiated by parasite antigen (eg GPI) involving CD8 CTL, macrophages and platelets may help disrupt BBB.
example of malaria natural immunity?
1 - with P.vivax.
2 - malaria needs to bind receptors to enter cells, P.vivax with duffy blood group antigens.
3 - high proportion of people in west africa are duffy negative so P.vivax cant infect.
example of malaria natural resistance?
1 - sickle cell anaemia. valine substituted for glutamic acid in beta-chain of globin causing defective haemoglobin (HbS).
2 - when HbS is deoxygenated in capillaries at low O2 tensions the RBC undergoes several changes inc distortion and loss of potassium causing parasite death.
3 - homozygous can be fatal but heterozygous confers protection against P.falciparum.
4 - also other RBC disorders:
- some thalassemias result in synth of abnormal alpha or beta globin chains which are believed to protect.
- glucose 6-phosphate dehydrogenase deficiency - may affect parasite growth or promote efficient phagocytosis of pRBCs.
- HLA associations - HLA-B53 = low risk association with severe anaemia. its MHC 1 presents liver stage and sporozoite stage antigens.
the adaptive response to malaria?
1 - 1 - complex, cell mediated and AB mediated. include:
- CD8 CTL response to liver cell stages.
- AB to sporozoites, merozoites and plasmodium proteins on RBCs eg PfEMP-1 to prevent cell invasion or promote phagocytosis/ complement mediated lysis.
factors contributing to malaria immune evasion?
1- repeated exposure slowely generates immunity and is often incomplete
2 - due to many facotrs inc - complex life cycle, antigenic diversity, and variation between species/strains/ each stage of development.
describe antigenic variation in malaria
many proteins exhibit it but best studied is PfEMP-1 coded by at least 50 var genes for the variants.
PfEMP-1 functions to avoid immunity/destruction via antigenic variation and sequestration.
another merozoite protein on RBCs is the highly polymorphic rif.
why is maternal malaria such an issue?
1 - a variant of PfEMP-1 in a sub-population of P.falciparum bind CSA which is highly expressed in the placenta. hence massively raised susceptability in first time mothers even if a natural immunity has been worked up over the preceding years.
