Pathogenesis of Cerebral Malaria: Inflammation, Cytoadherence And Recent Experimental Data For Humans

Rukhsana Kausar, Abier Javaid, Sidra Khan

Abstract


This study establishes that HRPII is a Plasmodium falciparum virulence factor that triggers an innate immune inflammatory response in vascular endothelium and contributes to cerebral malaria by compromising the integrity of the blood-brain barrier. Human malaria is caused by five species of Plasmodium. Of these, P. falciparum is the deadliest and is the only species that causes cerebral malaria (CM). CM is a disease of the vascular endothelium considered by parasite sequestration, increased inflammatory cytokine production, vascular leakage and leukocyte infiltration. A distinguishing feature of P. falciparum infection is the parasite’s production and secretion of histidine-rich protein II (HRPII). HRPII accumulates to high concentrations (up to 100 g/ml) in serum, which correlates with disease severity. Using a cellular model of the blood-brain barrier, it demonstrate that HRPII activates the innate immune system in human cerebral microvascular endothelial cells, resulting in redistribution of tight junction proteins and compromise of barrier integrity. Intravenous infusion of HRPII induced vascular leakage in the cerebellum and cortex of mice and increased early mortality in a P. berghei ANKA experimental cerebral malaria model. Analogously, transgenic P. berghei expressing falciparum HRPII produced more severe disease than wild-type or control P. berghei. HRPII induced endothelial expression of adhesion receptors used by plasmodium parasites, suggesting that this protein also contributes to pathogenesis by enhancing parasite cytoadherence and thereby avoiding splenic destruction. 


Keywords


Epidemiology, Pathophysiology, Cerebral Malaria, Mouse Models for Cerebral Malaria, HRPII, Blood Brain Barrier, Vascular endothelium, Inflammasome

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