Malaria Flashcards
(14 cards)
Causative agent?
Intracellular parasitic protozoa of the genus Plasmodium.
4 species cause malaria in humans, most common are P.falciparum & P.vivax
Transmitted to humans via mosquito vector.
See life cycle diagram p159
Clinical manifestations
Paroxysms of fever:
- becomes periodic
- peaks every other day in P.vivax, fluctuates more rapidly in P.falciparum
Headache, nausea
Anaemia
Splenomegaly
Sequestration of parasitized RBCs in brain & other organs (P. falciparum)
Hypoglycaemia & other metabolic disorders
Glomerulonephritis/ tubular necrosis
Blackwater fever, autoimmune haemolysis.
P.falciparum malaria
Multisystem disease
Most dangerous species- causes sever malaria including cerebral malaria (15-20% children die, even with treatment)
Cerebral malaria
Causes?
Definition?
Caused only by P.falciparum
Defined by clinical criteria: convulsion, impaired consciousness, unrousable coma.
Sequestration occurs in cerebral capillaries & veins -> - hypoxia - local endothelial injury & apoptosis - BBB dysfunction - brain swelling - intracranial hypertension may all be initiated.
Sequestration
Causes, location, consequences?
Mechanism?
Caused only by P.falciparum- modifies the surface of infected red cells.
Occurs in various organs: brain (NB cerebral malaria), heart, lung, liver, kidneys, placenta.
Prevents clearance of infected lymphocytes by spleen -> results in v high parasitemia.
Infected (modified to have knob-like projections) erythrocytes express PfPEMP-1 a parasitic protein on their surface:
- interacts with CD36, ICAM-1, VCAM-1, CSA on endothelial cells. RBCs can adhere to endothelial cells (c.f leukocyte adhesion)
- encoded by var gene family. Different variants are able to bind many different receptors.
Only P.falciparum sequesters, & only P.falciparum causes cerebral malaria- sequestration is fundamental to its ability to cause severe disease including cerebral malaria?
Cerebral malaria: cytokines
TNFα, IL-1, NO may contribute to symptoms of CM.
Parasite antigens/ toxins released when infected blood cells rupture-> triggers production of pro-& anti-inflam. cytokines.
e.g GPI:
- functions as membrane anchor for several merozoite membrane proteins.
- stimulates TNF production
TNF:
- may upregulate ICAM-1 expression on cerebral vascular endothelium -> increasing adhesion of pRBCs
- may upregulate expression of NO-> which may then cross BBB & interfere with neurotransmission
- involved in regulating synaptic transmission (strength, scaling, LTP)
Cerebral malaria: disruption of the BBB.
Disruption can contribute to intracranial hypertension & brain oedema.
Intracranial hypertension can lead to ischaemia & death.
Adherence of pRBCs to vascular endothelial cells initiates sequence of events that may lead to BBB breakdown, including:
- transcription of inflammatory cytokines
- endothelial activation or apoptosis
Inflammatory response to parasite antigens e.g GPI involving CD8 cells, macrophages & platelets is also thought to contribute.
Cerebral malaria: sequestration
Sequestration occurs in cerebral capillaries & veins
- considered to be a major factor in pathogenesis
- blood vessels may become blocked with parasitized erythrocytes -> hypoxia & inadequate tissue perfusion, necrosis if left untreated.
- objections to this mechanism: early work suggested that following specific antimalaria treatment, a high proportion of patients made a full recovery.
- however, more recent work has shown that many children do sustain significant brain injury, & 25% have long term impairments esp cognition, motor function/ behavioural impairments, epilepsy. Leading cause of neuro-disability in African children.
Natural immunity
People who are Duffy blood group antigen negative (high proportion in W.Africa) are immune to P.vivax.
Malaria parasites enter cells after interaction with specific receptors. P.vivax merozoites interact with Duffy blood group antigens.
Natural resistance
(4)
NB heterozygous conditions conferring resistance may be responsible for survival of alleles (fatal when homozygous) in the population.
Sickle cell anaemia (homozygous is fatal, heterozygous confers protection against severe P.falcipacum malaria)
- substitution of a valine for glutamic acid in the β chain of globin -> defective haemoglobin Hbs
- when HbS undergoes deoxygenation in capillaries at low oxygen tension, RBC becomes distorted & loses potassium-> parasite dies.
Various thalassemias resulting in synthesis of abnormal α or β globin chain.
Glucose-6-phosphate dehydrogenase deficiency: may affect parasite growth, or promote efficient phagocytosis of parasitised red cells.
HLA-B53 (class I) is associated with low risk of severe malaria. Presents liver-stage & sporozoite stage antigens to T cells.
Adaptive immune responses to malaria
Cytotixic CD8 T cell response to liver cell stages
Antibody response to sporozoites, merozoites & plasmodium proteins expressed on red cells (e.g PfEMP-1): prevent invasion of cells/ promote phagocytosis & complement-mediated lysis.
Immune evasion
Protective immunity in endemic regions takes many years to develop & may be incomplete, despite repeated exposure to malaria.
- antigenic variation & diversity between different plasmodium species, different strains of the same species, different stages e.g merozoite/sporotozite. At least 50 var genes encoding PfEMP-1. rif (another merozoite-encoded protin expressed on surface of pRBCs) is also highly polymorphic.
- specific T cell responses & in some cases even unrelated T cell responses may be down-regulated during course of infection.
- adhesion of malarial-infected erythrocytes to dendritic cells has been shown to inhibit DC maturation & reduce their capacity to stimulate T cells.
Susceptibility of pregnant women
Women are particularly susceptible to malaria during first pregnancies even though they may have developed resistance over many years in an endemic country.
- a sub-population of P.falciparum expresses a PfEMP-1 variant that binds CSA, which is highly expressed in the plaecenta (synctiotrophoblast)
Control of malaria
Reduction of human-mosquito contact: mosquito repellants, bed nets, house spraying
Reduction of vector breeding habits e.g drainage schemes, insecticides e.g DDT, larvicides e.g δ-endotoxin from Bacillus spps.
Attempts to create transgenic mosquitoes that are refractory to Plasmodium infection.
Chemotherapy- esp prophylactic for travellers. Attempting to develop vaccine, promosing sporozoite vaccine in trials.
