Shed EBA-175 mediates red blood cell clustering that enhances malaria parasite growth and enables immune evasion

Abstract

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.

Protein Modification Characteristics of the Malaria Parasite Plasmodium falciparum and the Infected Erythrocytes

“…The erythrocyte invasion pathway of P. falciparum can be either sialic acid–dependent or sialic acid–independent ( 5 ). The receptors of the sialic acid–dependent pathway include GPA, GPB, and GPC, which are glycophorins recognized by the parasite EBA family members ( 86 , 87 , 88 , 89 , 90 , 91 ). The receptors of sialic acid–independent invasion are CR1 ( 52 ), CD147/Basigin ( 92 ), Kx ( 90 ), CD44 ( 93 ), and CD55 ( 49 ).…”

Alternative Invasion Mechanisms and Host Immune Response to Plasmodium vivax Malaria: Trends and Future Directions

“…The role of the EBA-175 protein has been shown to be critical for erythrocyte invasion, as antibodies raised against EBA-175 prevent binding to GpA in vitro [ 60 , 61 ]. EBA-175 triggers changes in the erythrocyte membrane [ 62 , 63 ], and the shedding of EBA-175 causes uninfected red blood cells to cluster or form rosette, which allows for immune evasion [ 64 ]. The host immune responses may explain the polymorphisms and diversifying selection observed in EBA-175 [ 65 ].…”

Alternative Invasion Mechanisms and Host Immune Response to Plasmodium vivax Malaria: Trends and Future Directions

“…The role of the EBA-175 protein has been shown to be critical for erythrocyte invasion as antibodies raised against EBA-175 prevent binding to GpA in vitro [57,58]. EBA-175 triggers changes in the erythrocyte membrane [59,60] and shedding of EBA-175 causes uninfected red blood cells to cluster or form rosette that allows for immune evasion [61]. The host immune responses may explain the polymorphisms and diversifying selection observed in EBA-175 [62].…”