scholarly journals Suramin and Suramin Analogues Inhibit Merozoite Surface Protein-1 Secondary Processing and Erythrocyte Invasion by the Malaria ParasitePlasmodium falciparum

2003 ◽  
Vol 278 (48) ◽  
pp. 47670-47677 ◽  
Author(s):  
Suzanne L. Fleck ◽  
Berry Birdsall ◽  
Jeffrey Babon ◽  
Anton R. Dluzewski ◽  
Stephen R. Martin ◽  
...  
Keyword(s):  
Surface Protein ◽  
Merozoite Surface Protein ◽  
Secondary Processing ◽  
Merozoite Surface Protein 1 ◽  
Erythrocyte Invasion

scholarly journals Antibodies that Inhibit Malaria Merozoite Surface Protein–1 Processing and Erythrocyte Invasion Are Blocked by Naturally Acquired Human Antibodies

1997 ◽  
Vol 186 (10) ◽  
pp. 1689-1699 ◽  
Author(s):  
José A. Guevara Patiño ◽  
Anthony A. Holder ◽  
Jana S. McBride ◽  
Michael J. Blackman
Keyword(s):  
Inhibitory Activity ◽  
Surface Protein ◽  
Merozoite Surface Protein ◽  
Secondary Processing ◽  
Human Antibodies ◽  
Merozoite Surface Protein 1 ◽  
Erythrocyte Invasion ◽  
Endoproteolytic Cleavage ◽  
Inhibitory Antibodies ◽  
Blocking Antibodies

Merozoite surface protein–1 (MSP-1) of the human malaria parasite Plasmodium falciparum undergoes at least two endoproteolytic cleavage events during merozoite maturation and release, and erythrocyte invasion. We have previously demonstrated that mAbs which inhibit erythrocyte invasion and are specific for epitopes within a membrane-proximal, COOH-terminal domain of MSP-1 (MSP-119) prevent the critical secondary processing step which occurs on the surface of the extracellular merozoite at around the time of erythrocyte invasion. Certain other anti–MSP-119 mAbs, which themselves inhibit neither erythrocyte invasion nor MSP-1 secondary processing, block the processing-inhibitory activity of the first group of antibodies and are termed blocking antibodies. We have now directly quantitated antibody-mediated inhibition of MSP-1 secondary processing and invasion, and the effects on this of blocking antibodies. We show that blocking antibodies function by competing with the binding of processing-inhibitory antibodies to their epitopes on the merozoite. Polyclonal rabbit antibodies specific for certain MSP-1 sequences outside of MSP-119 also act as blocking antibodies. Most significantly, affinity-purified, naturally acquired human antibodies specific for epitopes within the NH2-terminal 83-kD domain of MSP-1 very effectively block the processing-inhibitory activity of the anti-MSP-119 mAb 12.8. The presence of these blocking antibodies also completely abrogates the inhibitory effect of mAb 12.8 on erythrocyte invasion by the parasite in vitro. Blocking antibodies therefore (a) are part of the human response to malarial infection; (b) can be induced by MSP-1 structures unrelated to the MSP-119 target of processing-inhibitory antibodies; and (c) have the potential to abolish protection mediated by anti–MSP-119 antibodies. Our results suggest that an effective MSP-119–based falciparum malaria vaccine should aim to induce an antibody response that prevents MSP-1 processing on the merozoite surface.

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 Antibodies inhibit the protease-mediated processing of a malaria merozoite surface protein.

1994 ◽  
Vol 180 (1) ◽  
pp. 389-393 ◽  
Author(s):  
M J Blackman ◽  
T J Scott-Finnigan ◽  
S Shai ◽  
A A Holder
Keyword(s):  
Malaria Parasite ◽  
Surface Protein ◽  
Merozoite Surface Protein ◽  
Secondary Processing ◽  
Erythrocyte Invasion ◽  
Parasite Plasmodium ◽  
Parasite Plasmodium Falciparum ◽  
Protective Antibodies ◽  
Epidermal Growth ◽  
Membrane Bound

When merozoites of the malaria parasite Plasmodium falciparum are released from infected erythrocytes and invade new red cells, a component of a protein complex derived from the merozoite surface protein 1 (MSP-1) precursor undergoes a single proteolytic cleavage known as secondary processing. This releases the complex from the parasite surface, except for a small membrane-bound fragment consisting of two epidermal growth factor (EGF)-like domains, which is the only part of MSP-1 to be carried into invaded erythrocytes. We report that, a group of monoclonal antibodies specific for epitopes within the EGF-like domains, some interfere with secondary processing whereas others do not. Those that most effectively inhibit processing have previously been shown to prevent invasion. Other antibodies, some of which can block this inhibition, not only do not prevent invasion but are carried into the host cell bound to the merozoite surface. These observations unequivocally demonstrate that the binding of antibody to the COOH-terminal region of MSP-1 on the merozoite surface may not be sufficient to prevent erythrocyte invasion, and show that the interaction of different antibodies with adjacent epitopes within the EGF-like domains of MSP-1 can have distinct biochemical effects on the molecule. Inhibition of MSP-1 processing on merozoites may be a mechanism by which protective antibodies interrupt the asexual cycle of the malaria parasite.

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 The Fine Specificity, but Not the Invasion Inhibitory Activity, of 19-Kilodalton Merozoite Surface Protein 1-Specific Antibodies Is Associated with Resistance to Malarial Parasitemia in a Cross-Sectional Survey in The Gambia

2004 ◽  
Vol 72 (10) ◽  
pp. 6185-6189 ◽  
Author(s):  
Patrick H. Corran ◽  
Rebecca A. O'Donnell ◽  
Jim Todd ◽  
Chairat Uthaipibull ◽  
Anthony A. Holder ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
Surface Protein ◽  
Merozoite Surface Protein ◽  
Ethnic Origin ◽  
Cross Sectional Survey ◽  
Cross Sectional ◽  
Fine Specificity ◽  
Merozoite Surface Protein 1 ◽  
Erythrocyte Invasion ◽  
Antibody Levels

ABSTRACT In a cross-sectional survey of 187 Gambian children and adults, we have analyzed prevalence, fine specificity, and 19-kilodalton merozoite surface protein 1 (MSP-119)-specific erythrocyte invasion inhibitory activity of antibodies to MSP-119 but find no significant association between any of these parameters and prevalence or density of malarial parasitemia, except that, after correcting for total anti-MSP-119 antibody levels, individuals with anti-MSP-119 antibodies that compete with an invasion inhibitory monoclonal antibody (12.10) were significantly less likely to have malaria infections with densities of ≥1,000 parasites/μl than were individuals without such antibodies. This association persisted after correction for age and ethnic origin.

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 The Human Immune Response to Plasmodium falciparum Includes Both Antibodies That Inhibit Merozoite Surface Protein 1 Secondary Processing and Blocking Antibodies

2002 ◽  
Vol 70 (9) ◽  
pp. 5328-5331 ◽  
Author(s):  
Roseangela I. Nwuba ◽  
Olugbemiro Sodeinde ◽  
Chiaka I. Anumudu ◽  
Yusuf O. Omosun ◽  
Alexander B. Odaibo ◽  
...  
Keyword(s):  
Malaria Infection ◽  
Surface Protein ◽  
Merozoite Surface Protein ◽  
Essential Step ◽  
Merozoite Surface Protein 1 ◽  
Erythrocyte Invasion ◽  
Human Immune Response ◽  
Inhibitory Antibodies ◽  
Human Immune ◽  
Blocking Antibodies

ABSTRACT Malaria merozoite surface protein 1 (MSP1) is cleaved in an essential step during erythrocyte invasion. The responses of children to natural malaria infection included antibodies that inhibit this cleavage and others that block the binding of these inhibitory antibodies. There was no correlation between the titer of the antibody to the 19-kDa fragment of MSP1 and its inhibitory activity. These findings have implications for the design of MSP1-based vaccines.

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