Shed EBA-175 mediates red blood cell clustering that enhances malaria parasite growth and enables immune evasion
May M Paing,
Nichole D Salinas,
Yvonne Adams,
Anna Oksman,
Anja TR Jensen,
Daniel E Goldberg,
Niraj H Tolia
Affiliations
May M Paing
Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, United States
Nichole D Salinas
Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, United States; Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, United States
Yvonne Adams
Centre for Medical Parasitology at Department of Immunology and Microbiology (ISIM), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Anna Oksman
Department of Medicine, Washington University School of Medicine, St. Louis, United States
Centre for Medical Parasitology at Department of Immunology and Microbiology (ISIM), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, United States; Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, United States
Erythrocyte Binding Antigen of 175 kDa (EBA-175) has a well-defined role in binding to glycophorin A (GpA) during Plasmodium falciparum invasion of erythrocytes. However, EBA-175 is shed post invasion and a role for this shed protein has not been defined. We show that EBA-175 shed from parasites promotes clustering of RBCs, and EBA-175-dependent clusters occur in parasite culture. Region II of EBA-175 is sufficient for clustering RBCs in a GpA-dependent manner. These clusters are capable of forming under physiological flow conditions and across a range of concentrations. EBA-175-dependent RBC clustering provides daughter merozoites ready access to uninfected RBCs enhancing parasite growth. Clustering provides a general method to protect the invasion machinery from immune recognition and disruption as exemplified by protection from neutralizing antibodies that target AMA-1 and RH5. These findings provide a mechanistic framework for the role of shed proteins in RBC clustering, immune evasion, and malaria.
