Rieger Harden, Yoshikawa Hiroshi Y, Quadt Katharina, Nielsen Morten A, Sanchez Cecilia P, Salanti Ali, Tanaka Motomu, Lanzer Michael
Department of Infectious Diseases, Parasitology, and Institute of Physical Chemistry, Physical Chemistry of Biosystems, Heidelberg University, Heidelberg, Germany;
Institute of Physical Chemistry, Physical Chemistry of Biosystems, Heidelberg University, Heidelberg, Germany; Department of Chemistry, Saitama University, Saitama, Japan;
Blood. 2015 Jan 8;125(2):383-91. doi: 10.1182/blood-2014-03-561019. Epub 2014 Oct 28.
Infections with the human malaria parasite Plasmodium falciparum during pregnancy can lead to severe complications for both mother and child, resulting from the cytoadhesion of parasitized erythrocytes in the intervillous space of the placenta. Cytoadherence is conferred by the specific interaction of the parasite-encoded adhesin VAR2CSA with chondroitin-4-sulfate (CSA) present on placental proteoglycans. CSA presented elsewhere in the microvasculature does not afford VAR2CSA-mediated cytoadhesion of parasitized erythrocytes. To address the placenta-specific binding tropism, we investigated the effect of the receptor/ligand arrangement on cytoadhesion, using artificial membranes with different CSA spacing intervals. We found that cytoadhesion is strongly dependent on the CSA distance, with half-maximal adhesion occurring at a CSA distance of 9 ± 1 nm at all hydrodynamic conditions. Moreover, binding to CSA was cooperative and shear stress induced. These findings suggest that the CSA density, together with allosteric effects in VAR2CSA, aid in discriminating between different CSA milieus.
孕期感染人类疟原虫恶性疟原虫可导致母婴出现严重并发症，这是由寄生红细胞在胎盘绒毛间隙的细胞黏附所致。细胞黏附是由寄生虫编码的黏附素VAR2CSA与胎盘蛋白聚糖上存在的硫酸软骨素-4（CSA）的特异性相互作用介导的。在微血管其他部位呈现的CSA并不能使寄生红细胞发生VAR2CSA介导的细胞黏附。为了研究胎盘特异性结合趋向性，我们使用具有不同CSA间距间隔的人工膜研究了受体/配体排列对细胞黏附的影响。我们发现细胞黏附强烈依赖于CSA距离，在所有流体动力学条件下，当CSA距离为9±1nm时出现半数最大黏附。此外，与CSA的结合具有协同性且受剪切应力诱导。这些发现表明，CSA密度以及VAR2CSA中的变构效应有助于区分不同的CSA环境。
