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

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