Department of Molecular Hematology, Sanquin Research and Landsteiner Laboratory, Amsterdam, The Netherlands.
Department of Product and Process Development, Sanquin Research and Landsteiner Laboratory, Amsterdam, The Netherlands.
Blood Adv. 2022 Nov 8;6(21):5798-5810. doi: 10.1182/bloodadvances.2021006171.
Severe malarial anemia (SMA) is the main cause of malaria-associated infant mortality in malaria endemic countries. One major factor that contributes to SMA is the accumulation of uninfected red blood cells (uRBCs) in the spleen. We report the activation of adhesion molecules Lutheran/basal cell adhesion molecule (Lu/BCAM) and CD44 on uRBCs from Plasmodium falciparum in vitro cultures and patients with malaria that mediates adherence to the splenic extracellular matrix (ECM) components laminin-α5 and hyaluronic acid (HA), respectively. This tight ECM-adhesion molecule interaction was associated with elevated intracellular Ca2+ levels, increased shedding of microvesicles, and Lu/BCAM clustering on altered uRBCs. Moreover, we observed that a soluble parasite-derived factor promoted the adhesive phenotype of uRBCs, as the incubation of RBCs with filtered malaria-conditioned medium reproduced the same adhesive effect in malaria culture-derived uRBCs. Eventually, Lu/BCAM and CD44 activation facilitate the adherence to ECM components of the red pulp, resulting in the enhanced splenic retention of uRBCs. Our results suggest a novel adhesion molecule-dependent mechanism that augments malaria-induced anemia.
严重疟疾性贫血（SMA）是疟疾流行国家中与疟疾相关的婴儿死亡的主要原因。导致 SMA 的一个主要因素是脾脏中未感染的红细胞（uRBC）的积累。我们报告了在体外培养的疟原虫和疟疾患者的 uRBC 上 Lutheran/基底细胞粘附分子（Lu/BCAM）和 CD44 粘附分子的激活，分别介导与脾脏细胞外基质（ECM）成分层粘连蛋白-α5 和透明质酸（HA）的粘附。这种紧密的 ECM-粘附分子相互作用与细胞内 Ca2+水平升高、微囊泡脱落增加以及 Lu/BCAM 在改变的 uRBC 上的聚集有关。此外，我们观察到一种可溶性寄生虫衍生因子促进了 uRBC 的粘附表型，因为用过滤的疟疾条件培养基孵育 RBC 可在疟疾培养衍生的 uRBC 中再现相同的粘附作用。最终，Lu/BCAM 和 CD44 的激活促进了 uRBC 对红髓 ECM 成分的粘附，从而增强了 uRBC 在脾脏中的滞留。我们的结果表明了一种新的粘附分子依赖性机制，增强了疟疾引起的贫血。
