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all erythrocytes invaded Pv/Po = reticulocytes Pm = senescent RBC up to 36 merozoites

Higher Parasitemia in Falciparum Malaria. 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

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all erythrocytes invaded Pv/Po = reticulocytes Pm = senescent RBC up to 36 merozoites

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  1. Higher Parasitemia in Falciparum Malaria • 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)

  2. avoidance of spleen • low oxygen tensions • better invasion

  3. Severe Falciparum Malaria

  4. 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

  5. P. falciparum expresses ‘knobs’ on the surface of infected erythrocytes. Knobs mediate cytoadherence to endothelial cells.

  6. 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

  7. PfEMP-1 Structure • 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 (a, b, g, d, e) • 1-2 cys-rich interdomain regions • all have DBL1a + CIDR • participates in cytoadherence

  8. Possible Host Receptors • 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

  9. Sequestration Hypothesis cytoadherence  cerebral ischemia  hypoxia, metabolic effects  coma  death

  10. Problems with Sequestration Hypothesis • rapid reversibility • lack of ischemic damage • low levels of permanent neurological damage • sequestration occurs in non-cerebral malaria cases

  11. Cytokine Theory

  12. Cytokine Theory Problem • minimal lymphocyte infil-tration or inflammation

  13. Severe falciparum malaria • potentially high parasitemias • sequestration • complex (and not fully understood) host-parasite interactions

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