Cerebral Malaria severe complication of falciparum malaria mortality of 30-50% associated with sequestration in micro- vasculature of brain a diffuse encephalopathy with loss of consciousness consciousness ranges from stupor to coma unresponsive to pain, visual, and verbal stimuli convulsions frequently observed onset can be gradual or sudden

Complications Associated with Falciparum Malaria cerebral malaria anemia hyperpyrexia hypoglycemia acidosis GI and liver syndromes pulmonary edema blackwater fever algid malaria (shock)

Features Indicating Poor Prognosis in Severe Malaria impaired consciousness repeated convulsions respiratory distress shock acidosis/hyperlactemia hypoglycemia jaundice or other liver malfunctions renal impairment high parasitemia (>500,000/mm 3 )

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 Higher Parasitemias in Falciparum Malaria

avoidance of spleen low oxygen tensions better invasion

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 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

Sequestration Hypothesis cytoadherence cerebral ischemia hypoxia, metabolic effects coma death

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

Cytokine Theory

Cytokine Theory Problem minimal lymphocyte infil- tration or inflammation

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