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Abstract
The ability of Plasmodium falciparum–infected red blood cells (IRBCs) to bind to vascular endothelium, thus enabling sequestration in vital host organs, is an important pathogenic mechanism in malaria. Adhesion of P. falciparum IRBCs to platelets, which results in the formation of IRBC clumps, is another cytoadherence phenomenon that is associated with severe disease. Here, we have used in vitro cytoadherence assays to demonstrate, to our knowledge for the first time, that P. falciparum IRBCs use the 32-kDa human protein gC1qR/HABP1/p32 as a receptor to bind to human brain microvascular endothelial cells. In addition, we show that P. falciparum IRBCs can also bind to gC1qR/HABP1/p32 on platelets to form clumps. Our study has thus identified a novel host receptor that is used for both adhesion to vascular endothelium and platelet-mediated clumping. Given the association of adhesion to vascular endothelium and platelet-mediated clumping with severe disease, adhesion to gC1qR/HABP1/p32 by P. falciparum IRBCs may play an important role in malaria pathogenesis.
Highlights
Malaria continues to be a major public health problem in many parts of the tropical world, with approximately 500 million malaria cases reported annually that result in 1–2 million deaths every year [1,2]
Expression of intercellular adhesion molecule-1 (ICAM-1) is upregulated on cerebrovascular endothelium [5,23], and P. falciparum infected red blood cell (IRBC) co-localize with ICAM-1 in cerebral vessels of patients who die of cerebral malaria [23], suggesting that adhesion to ICAM-1 plays a key role in cerebral sequestration
Adhesion of Plasmodium falciparum–infected red blood cells (IRBCs) to the endothelium lining the capillaries of vital host organs can obstruct blood circulation and is an important pathogenic mechanism in malaria
Summary
Malaria continues to be a major public health problem in many parts of the tropical world, with approximately 500 million malaria cases reported annually that result in 1–2 million deaths every year [1,2]. Adhesion of IRBCs to vascular endothelium is mediated by interaction of the P. falciparum erythrocyte membrane protein-1 (PfEMP-1) family of variant surface antigens with host receptors [11,12,13]. Expression of ICAM-1 is upregulated on cerebrovascular endothelium [5,23], and P. falciparum IRBCs co-localize with ICAM-1 in cerebral vessels of patients who die of cerebral malaria [23], suggesting that adhesion to ICAM-1 plays a key role in cerebral sequestration. Platelets, which have been shown to accumulate in brain microvasculature of patients who die of cerebral malaria, express CD36 on their surface and may act as bridges for adhesion of P. falciparum IRBCs with brain vascular endothelium [27,28,29]. In previous studies, antibodies to CD36 could not completely
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