Malaria-associated adhesion molecule activation facilitates the destruction of uninfected red blood cells

TY - JOUR

T1 - Malaria-associated adhesion molecule activation facilitates the destruction of uninfected red blood cells

AU - Dalimot, Jill J

AU - Klei, Thomas R L

AU - Beuger, Boukje M

AU - Dikmen, Zeynep

AU - Bouwman, Suzan A M

AU - Mombo-Ngoma, Ghyslain

AU - Zoleko-Manego, Rella

AU - Ndzebe-Ndoumba, Wilfrid F

AU - Egée, Stéphane

AU - Kuijpers, Taco W

AU - Grobusch, Martin P

AU - van Bruggen, Robin

N1 - © 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.

PY - 2022/11/8

Y1 - 2022/11/8

N2 - 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.

AB - 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.

KW - Humans

KW - Lutheran Blood-Group System/metabolism

KW - Anemia, Sickle Cell

KW - Cell Adhesion Molecules/genetics

KW - Erythrocytes/metabolism

KW - Malaria

U2 - 10.1182/bloodadvances.2021006171

DO - 10.1182/bloodadvances.2021006171

M3 - SCORING: Journal article

C2 - 35349634

VL - 6

SP - 5798

EP - 5810

JO - BLOOD ADV

JF - BLOOD ADV

SN - 2473-9529

IS - 21

ER -