all erythrocytes invaded Pv/Po = reticulocytes Pm = senescent RBC up to 36 merozoites sequestration...
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Transcript of all erythrocytes invaded Pv/Po = reticulocytes Pm = senescent RBC up to 36 merozoites sequestration...
Disease Severity Pv Po Pm Pf Average (per mm3)
20,000 9,000 6,000 50,000-500,000
Maximum (per mm3)
50,000 30,000 20,000 2,500,000
Paroxysm Severity
moderate to severe
mild mild to
moderate severe
Duration Disease (average) Infection (maximum)
3-8 w
5-8 y
2-3 w
12-20 m
3-24 w
>20 y
2-3 w
6-17 m
Anemia ++ + ++ ++++
Complications renal cerebral +
others
• all erythrocytes invaded• Pv/Po = reticulocytes• Pm = senescent RBC
• up to 36 merozoites• sequestration of
infected erythrocytes • trophozoite and schizont
stages• primarily in brain, heart,
lungs, and gut• complications• immune evasion (spleen
avoidance)
Higher Parasitemia in Falciparum Malaria
• avoidance of spleen• low oxygen tensions• better invasion
Severe Falciparum Malaria
ComplicationsFeatures Indicating Poor Prognosis
•cerebral malaria•anemia•hyperpyrexia•hypoglycemia •acidosis•GI and liver syndromes•pulmonary edema•blackwater fever•algid malaria (shock)
•impaired consciousness•repeated convulsions•respiratory distress•shock•acidosis/hyperlactemia•hypoglycemia•jaundice or other liver malfunctions•renal impairment•high parasitemia (>500,000/mm3)
Cerebral Malaria•severe complication of falciparum malaria
• mortality of 30-50%•a diffuse encephalopathy with loss of consciousness• severe headache followed by drowsiness,
confusion and coma • consciousness ranges from stupor to coma• unresponsive to pain, visual, and verbal stimuli• convulsions frequently observed• onset can be gradual or sudden
•associated with sequestration in micro-vasculature of brain
P. falciparum expresses ‘knobs’ on the surface of infected erythrocytes. Knobs mediate cytoadherence to endothelial cells.
Several Parasite Proteins Are Associated with Knobs
• KAHRP and PfEMP2 are believed to interact with the submembrane cytoskeleton of the host erythrocyte
• reorganization of the membrane skeleton may result in knob formation
• PfEMP1 crosses the erythrocyte membrane and is exposed on the surface
• family of 40-50 var genes• conserved intracellular C-terminus
• acidic terminal segment (ATS)• binds cytoskeleton + KAHRP
• transmembrane domain• variable extracellular domain
composed of modules• 2-7 copies of Duffy-binding like
domains • 5 sequence types ()
• 1-2 cys-rich interdomain regions• all have DBL1 + CIDR
• participates in cytoadherence
PfEMP-1 Structure
• CD36• Ig super-family
• ICAM-1• VCAM-1• PECAM-1
• E-selectin• thrombospondin• chondroitin sulfate A• hyaluronic acid
• Rosetting Receptors• CR-1• glycosaminoglycan• blood group A
Possible Host Receptors
Binding SitesDomain ReceptorCIDR CD36
DBL rosetting
DBL ICAM-1
DBL CSA
SequestrationHypothesis
cytoadherence
cerebral ischemia
hypoxia, metabolic effects
coma
death
Neurological Sequelae AmongSurvivors of Cerebral Malaria
at discharge 23.3%
at 1 month 8.6%
at 6 months 4.4%van Hansbroek et al (1997) J. Pediatrics 131:125
Problems with Sequestration Hypothesis
• rapid reversibility• lack of ischemic damage• low levels of permanent
neurological damage• sequestration occurs in
non-cerebral malaria cases
Cytokine Theoryexo-
antigens TNF +
IL-1 nitric
oxide coma,
death
Cytokine Theory Problem• minimal lymphocyte infil-
tration or inflammation
Severe falciparum malaria
• potentially high parasitemias• sequestration• complex (and not fully understood)
host-parasite interactions