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

Author:

Dalimot Jill J.1ORCID,Klei Thomas R.L.2,Beuger Boukje M.1,Dikmen Zeynep1,Bouwman Suzan A.M.34,Mombo-Ngoma Ghyslain456ORCID,Zoleko-Manego Rella46,Ndzebe-Ndoumba Wilfrid F.4ORCID,Egée Stéphane7,Kuijpers Taco W.18ORCID,Grobusch Martin P.345,van Bruggen Robin1

Affiliation:

1. 1Department of Molecular Hematology, Sanquin Research and Landsteiner Laboratory, Amsterdam, The Netherlands

2. 2Department of Product and Process Development, Sanquin Research and Landsteiner Laboratory, Amsterdam, The Netherlands

3. 3Center of Tropical Medicine and Travel Medicine, Department of Infectious Diseases, Division of Internal Medicine, Amsterdam University Medical Centers (AMC), Amsterdam Infection and Immunity, Amsterdam Public Health, University of Amsterdam, Amsterdam, The Netherlands

4. 4Centre de Recherches Médicales de Lambaréné (CERMEL), Lambaréné, Gabon

5. 5Institute for Tropical Medicine, University of Tübingen and German Center for Infection Research (DZIF), Tübingen, Germany

6. 6Department of Tropical Medicine, Bernhard Nocht Institute for Tropical Medicine and Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

7. 7Team Compared Physiology of Erythrocytes, CNRS (Centre National de la Recherche Scientifique) UPMC (Université Pierre-et-Marie-Curie), Station Biologique de Roscoff, Roscoff, France

8. 8Department of Pediatric Immunology, Rheumatology and Infectious Disease, Emma Children’s Hospital, AMC, Amsterdam, The Netherlands

Abstract

AbstractSevere 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.

Publisher

American Society of Hematology

Subject

Hematology

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