A Co-ligand Complex Anchors Plasmodium falciparum Merozoites to the Erythrocyte Invasion Receptor Band 3

Abstract

In Plasmodium falciparum malaria, erythrocyte invasion by circulating merozoites may occur via two distinct pathways involving either a sialic acid-dependent or -independent mechanism. Earlier, we identified two nonglycosylated exofacial regions of erythrocyte band 3 termed 5ABC and 6A as an important host receptor in the sialic acid-independent invasion pathway. 5ABC, a major segment of this receptor, interacts with the 42-kDa processing product of merozoite surface protein 1 (MSP1 42 ) through its 19-kDa C-terminal domain. Here, we show that two regions of merozoite surface protein 9 (MSP9), also known as acidic basic repeat antigen, interact directly with 5ABC during erythrocyte invasion by P. falciparum. Native MSP9 as well as recombinant polypeptides derived from two regions of MSP9 (MSP9/⌬1 and MSP9/⌬2) interacted with both 5ABC and intact erythrocytes. Soluble 5ABC added to the assay mixture drastically diminished the binding of MSP9 to erythrocytes. Recombinant MSP9/⌬1 and MSP9/⌬2 present in the culture medium blocked P. falciparum reinvasion into erythrocytes in vitro. Native MSP9 and MSP1 42 , the two ligands binding to the 5ABC receptor, existed as a stable complex. Our results establish a novel concept wherein the merozoite exploits a specific complex of co-ligands on its surface to target a single erythrocyte receptor during invasion. This new paradigm poses a new challenge in the development of a vaccine for blood stage malaria.

A new release on life: emerging concepts in proteolysis and parasite invasion

“…This is an appealing notion, given the known involvement of EGF-like modules in many protein-protein interactions, but there is little supporting evidence for it. As mentioned above, there are indications that the C-terminal part of MSP1 binds directly or indirectly to host cell receptors at invasion (Goel et al, 2003;Li et al, 2004), but no hint that this requires -or is enhanced by -secondary processing. Furthermore, recent work by Crabb and colleagues showing that the P. falciparum and Plasmodium chabaudi MSP-1 19 domains can be replaced by even highly divergent sequences without any detrimental effect on parasite replication argues for a predominantly structural role for MSP-1 19 (O'Donnell et al, 2000;Drew et al, 2004).…”

“…Among the surface antigens, Plasmodium merozoite surface protein-1 (MSP1) represents by far the most well-documented example of primary processing. Plasmodium falciparum MSP1 (PfMSP1) is an approximately 200 kDa surface antigen that forms a noncovalent complex with MSP6, MSP7 and MSP9 (Pachebat et al ., 2001;Trucco et al ., 2001;Li et al ., 2004). During or just before merozoite release (the precise timing has not been unambiguously established), MSP1 is proteolytically processed into fragments of 83, 30, 38 and 42 kDa (in order from the N-to C-terminus).…”

“…1B) whereas capping is observed for apical invasion proteins. Shaving occurs continuously as the parasite penetrates and is (Dubremetz et al ., 1985;Grimwood and Smith, 1995) Yes (Mineo and Kasper, 1994;He et al ., 2002) Unknown TgMIC1/MIC4/MIC6 (Meissner et al ., 2002b) Yes (Fourmaux et al ., 1996;Brecht et al ., 2001) MPP1 TgMIC2/M2AP Yes (Carruthers et al ., 1999;Harper et al ., 2004) MPP1 Zhou et al ., 2004) TgMIC3/MIC8 (Meissner et al ., 2002b) Yes (Garcia-Reguet et al ., 2000;Meissner et al ., 2002b) MPP1 TgAMA1 (Donahue et al ., 2000;Hehl et al ., 2000) Unknown MPP1 (S. A. Howell, M. J. Blackman and V. B. Carruthers, unpublished) Plasmodium PfTRAP and PbTRAP (Bhanot et al, 2003;Silvie et al ., 2004) Yes (McCormick et al ., 1999;Akhouri et al ., 2004) Serine protease (Silvie et al .. 2004) PfCSP (Stewart and Vanderberg, 1988; Yes (Pinzon-Ortiz et al ., 2001) Unknown PfMSP1/MSP6/MSP7 (Stafford et al ., 1994) Yes (Goel et al ., 2003;Li et al ., 2004) MESH (Howell et al ., 2003) PkAMA1 and PfAMA1 (Deans et al ., 1984;Howell et al ., 2001) Yes (Fraser et al ., 2001) MESH (Howell et al ., 2003) EBL-DBP (Camus and Hadley, 1985;Haynes et al ., 1988) Yes (Camus and Hadley, 1985;Haynes et al ., 1988) Unknown Py235 (Ogun and Holder, 1996) Yes (Ogun and Holde...…”

Merozoite surface protein 1 recognition of host glycophorin A mediates malaria parasite invasion of red blood cells

“…11 Our previous studies demonstrated a biochemical and functional interaction between host RBC band 3 and P falciparum 42-kDa and 19-kDa fragments of MSP1. 12,13 The obligatory role of MSP1 in malaria parasite invasion of RBCs 14 suggests that other MSP1 segments may recognize cognate host receptors, thus serving as targets of an effective immune response against malaria.…”

“…12,13,41 Host band 3 is the most abundant membrane protein in RBCs and forms a tight stoichiometric complex with GPA. Like band 3, GPA is also highly abundant and serves as a sialic acid-dependent receptor, binding the parasite ligand 42 On the basis of these observations, we hypothesized that merozoites may display ligands that can potentially bind to band 3 and GPA simultaneously, thus integrating distinct invasion pathways.…”