scholarly journals Inhibition of Erythrocyte Invasion and Plasmodium falciparum Merozoite Surface Protein 1 Processing by Human Immunoglobulin G1 (IgG1) and IgG3 Antibodies

2009 ◽  
Vol 77 (12) ◽  
pp. 5659-5667 ◽  
Author(s):  
Maria Lazarou ◽  
José A. Guevara Patiño ◽  
Richard M. Jennings ◽  
Richard S. McIntosh ◽  
Jianguo Shi ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Dna Sequences ◽  
Surface Protein ◽  
Merozoite Surface Protein ◽  
Amino Acid Sequences ◽  
Human Immunoglobulin ◽  
Human Neutrophils ◽  
Merozoite Surface Protein 1 ◽  
Erythrocyte Invasion ◽  
Carboxy Terminal

ABSTRACT Antigen-specific antibodies (Abs) to the 19-kDa carboxy-terminal region of Plasmodium falciparum merozoite surface protein 1 (MSP119) play an important role in protective immunity to malaria. Mouse monoclonal Abs (MAbs) 12.10 and 12.8 recognizing MSP119 can inhibit red cell invasion by interfering with MSP1 processing on the merozoite surface. We show here that this ability is dependent on the intact Ab since Fab and F(ab′)2 fragments derived from MAb 12.10, although capable of binding MSP1 with high affinity and competing with the intact antibody for binding to MSP1, were unable to inhibit erythrocyte invasion or MSP1 processing. The DNA sequences of the variable (V) regions of both MAbs 12.8 and 12.10 were obtained, and partial amino acid sequences of the same regions were confirmed by mass spectrometry. Human chimeric Abs constructed by using these sequences, which combine the original mouse V regions with human γ1 and γ3 constant regions, retain the ability to bind to both parasites and recombinant MSP119, and both chimeric human immunoglobulin G1s (IgG1s) were at least as good at inhibiting erythrocyte invasion as the parental murine MAbs 12.8 and 12.10. Furthermore, the human chimeric Abs of the IgG1 class (but not the corresponding human IgG3), induced significant NADPH-mediated oxidative bursts and degranulation from human neutrophils. These chimeric human Abs will enable investigators to examine the role of human Fcγ receptors in immunity to malaria using a transgenic parasite and mouse model and may prove useful in humans for neutralizing parasites as an adjunct to antimalarial drug therapy.

scholarly journals Analysis of Antibodies Directed against Merozoite Surface Protein 1 of the Human Malaria Parasite Plasmodium falciparum

2006 ◽  
Vol 74 (2) ◽  
pp. 1313-1322 ◽  
Author(s):  
Ute Woehlbier ◽  
Christian Epp ◽  
Christian W. Kauth ◽  
Rolf Lutz ◽  
Carole A. Long ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Surface Protein ◽  
Merozoite Surface Protein ◽  
Merozoite Surface Protein 1 ◽  
Erythrocyte Invasion ◽  
Parasite Plasmodium ◽  
Parasite Plasmodium Falciparum ◽  
Parasite Multiplication ◽  
Parasite Replication

ABSTRACT The 190-kDa merozoite surface protein 1 (MSP-1) of Plasmodium falciparum, an essential component in the parasite's life cycle, is a primary candidate for a malaria vaccine. Rabbit antibodies elicited by the heterologously produced MSP-1 processing products p83, p30, p38, and p42, derived from strain 3D7, were analyzed for the potential to inhibit in vitro erythrocyte invasion by the parasite and parasite growth. Our data show that (i) epitopes recognized by antibodies, which inhibit parasite replication, are distributed throughout the entire MSP-1 molecule; (ii) when combined, antibodies specific for different regions of MSP-1 inhibit in a strictly additive manner; (iii) anti-MSP-1 antibodies interfere with erythrocyte invasion as well as with the intraerythrocytic growth of the parasite; and (iv) antibodies raised against MSP-1 of strain 3D7 strongly cross-inhibit replication of the heterologous strain FCB-1. Accordingly, anti-MSP-1 antibodies appear to be capable of interfering with parasite multiplication at more than one level. Since the overall immunogenicity profile of MSP-1 in rabbits closely resembles that found in sera of Aotus monkeys immunized with parasite-derived MSP-1 and of humans semi-immune to malaria from whom highly inhibiting antigen-specific antibodies were recovered, we consider the findings reported here to be relevant for the development of MSP-1-based vaccines against malaria.

scholarly journals Plasmodium falciparum Merozoite Surface Protein 6 Is a Dimorphic Antigen

2004 ◽  
Vol 72 (4) ◽  
pp. 2321-2328 ◽  
Author(s):  
J. Andrew Pearce ◽  
Tony Triglia ◽  
Anthony N. Hodder ◽  
David C. Jackson ◽  
Alan F. Cowman ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Protein Structures ◽  
Surface Protein ◽  
Merozoite Surface Protein ◽  
Surface Proteins ◽  
Parasite Line ◽  
Merozoite Surface Protein 1 ◽  
Erythrocyte Invasion ◽  
Falciparum Merozoite ◽  
Asexual Cycle

ABSTRACT Merozoite surface protein 1 (MSP1) is a highly polymorphic Plasmodium falciparum merozoite surface protein implicated in the invasion of human erythrocytes during the asexual cycle. It forms a complex with MSP6 and MSP7 on the merozoite surface, and this complex is released from the parasite around the time of erythrocyte invasion. MSP1 and many other merozoite surface proteins contain dimorphic elements in their protein structures, and here we show that MSP6 is also dimorphic. The sequences of eight MSP6 genes indicate that the alleles of each dimorphic form of MSP6 are highly conserved. The smaller 3D7-type MSP6 alleles are detected in parasites from all malarious regions of the world, whereas K1-type MSP6 alleles have only been detected in parasites from mainland Southeast Asia. Cleavage of MSP6, which produces the p36 fragment in 3D7-type MSP6 and associates with MSP1, also occurs in K1-type MSP6 but at a different site in the protein. Anti-3D7 MSP6 antibodies weakly inhibited erythrocyte invasion by homologous 3D7 merozoites but did not inhibit a parasite line expressing the K1-type MSP6 allele. Antibodies from hyperimmune individuals affinity purified on an MSP3 peptide cross-reacted with MSP6; therefore, MSP6 may also be a target of antibody-dependent cellular inhibition.

scholarly journals Extensive Antigenic Polymorphism within the Repeat Sequence of the Plasmodium falciparum Merozoite Surface Protein 1 Block 2 Is Incorporated in a Minimal Polyvalent Immunogen

2005 ◽  
Vol 73 (9) ◽  
pp. 5928-5935 ◽  
Author(s):  
Kevin K. A. Tetteh ◽  
David R. Cavanagh ◽  
Patrick Corran ◽  
Rosemary Musonda ◽  
Jana S. McBride ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Single Molecule ◽  
Surface Protein ◽  
Merozoite Surface Protein ◽  
Repeat Sequence ◽  
Allelic Polymorphism ◽  
Length Variation ◽  
Candidate Sequence ◽  
Merozoite Surface Protein 1 ◽  
Allelic Sequence

ABSTRACT Polymorphism in pathogen antigens presents a complex challenge for vaccine design. A prime example is the N-terminal block 2 region of the Plasmodium falciparum merozoite surface protein 1 (MSP1), to which allele-specific antibodies have been associated with protection from malaria. In a Zambian population studied here, 49 of 91 alleles sampled were of the K1-like type (the most common of three block 2 types in all African populations), and most of these had unique sequences due to variation in tri- and hexapeptide repetitive motifs. There were significant negative correlations between allelic sequence lengths of different regions of the repeats, so the complete repeat sequence had less length variation than its component parts, suggesting a constraint on overall length. Diverse epitopes recognized by three murine monoclonal antibodies and 24 individual human sera were then mapped by using a comprehensive panel of synthetic peptides, revealing epitopes in all regions of the repeats. To incorporate these different epitopes in a single molecule, a composite sequence of minimal overall length (78 amino acids) was then designed and expressed as a recombinant antigen. More human immune sera reacted with this “K1-like Super Repeat” antigen than with proteins consisting of single natural allelic sequences, and immunization of mice elicited antibodies that recognized a range of five cultured parasite lines with diverse K1-like MSP1 block 2 repeat sequences. Thus, complex allelic polymorphism was deconstructed and a minimal composite polyvalent antigen was engineered, delivering a designed candidate sequence for inclusion in a malaria vaccine.

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