scholarly journals A single fragment of a malaria merozoite surface protein remains on the parasite during red cell invasion and is the target of invasion-inhibiting antibodies.

1990 ◽  
Vol 172 (1) ◽  
pp. 379-382 ◽  
Author(s):  
M J Blackman ◽  
H G Heidrich ◽  
S Donachie ◽  
J S McBride ◽  
A A Holder
Keyword(s):  
Cell Invasion ◽  
Surface Protein ◽  
Merozoite Surface Protein ◽  
Red Cell ◽  
Small Fragment ◽  
Erythrocyte Invasion ◽  
Single Fragment

A complex of polypeptides derived from a precursor is present on the surface of the malaria merozoite. During erythrocyte invasion only a small fragment from this complex is retained on the parasite surface and carried into the newly infected red cell. Antibodies to this fragment will interrupt invasion.

scholarly journals Distinct Th1- and Th2-Type Prenatal Cytokine Responses to Plasmodium falciparum Erythrocyte Invasion Ligands

2005 ◽  
Vol 73 (6) ◽  
pp. 3462-3470 ◽  
Author(s):  
Indu Malhotra ◽  
Peter Mungai ◽  
Eric Muchiri ◽  
John Ouma ◽  
Shobhona Sharma ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Cord Blood ◽  
Interleukin 2 ◽  
Surface Protein ◽  
Merozoite Surface Protein ◽  
Cd8 Cells ◽  
Erythrocyte Invasion ◽  
Cytokine Responses ◽  
Th1 And Th2 Responses ◽  
Th1 And Th2

ABSTRACT Prenatal immunity to Plasmodium falciparum merozoite proteins involved in erythrocyte invasion may contribute to the partial protection against malaria that is acquired during infancy in areas of stable malaria transmission. We examined newborn and maternal cytokine and antibody responses to merozoite surface protein-1 (MSP-1), ribosomal phosphoprotein P0 (PfP0), and region II of erythrocyte binding antigen-175 (EBA-175) in infant-mother pairs in Kenya. Overall, 82 of 167 (50%), 106 of 176 (60%), and 38 of 84 (45%) cord blood lymphocytes (CBL) from newborns produced one or more cytokines in response to MSP-1, PfP0, and EBA-175, respectively. Newborns of primigravid and/or malaria-infected women were more likely to have antigen-responsive CBL than were newborns of multigravid and/or uninfected women at delivery. Newborn cytokine responses did not match those of their mothers and fell into three distinct categories, Th1 (21 of 55 CBL donors produced only gamma interferon and/or interleukin 2 [IL-2]), Th2 (21 of 55 produced only IL-5 and/or IL-13), and mixed Th1/Th2 (13 of 55). Newborns produced more IL-10 than adults. High and low levels of cord blood IL-12 p70 production induced by anti-CD40 activation were associated with malaria-specific Th1 and Th2 responses, respectively. Antigen-responsive CBL in some newborns were detected only after depletion of IL-10-secreting CD8 cells with enrichment for CD4 cells. These data indicate that prenatal sensitization to blood-stage Plasmodium falciparum occurs frequently in areas where malaria is holoendemic. Modulation of this immunity, possibly by maternal parity and malaria, may affect the acquisition of protective immunity against malaria during infancy.

scholarly journals Antimalarial Activity of Cupredoxins

2013 ◽  
Vol 288 (29) ◽  
pp. 20896-20907 ◽  
Author(s):  
Isabel Cruz-Gallardo ◽  
Irene Díaz-Moreno ◽  
Antonio Díaz-Quintana ◽  
Antonio Donaire ◽  
Adrián Velázquez-Campoy ◽  
...  
Keyword(s):  
Blood Cell ◽  
Red Blood Cell ◽  
Antimalarial Activity ◽  
Surface Protein ◽  
Merozoite Surface Protein ◽  
Food Vacuole ◽  
Parasite Growth ◽  
Titration Calorimetry ◽  
Erythrocyte Invasion ◽  
Promising Target

The discovery of effective new antimalarial agents is urgently needed. One of the most frequently studied molecules anchored to the parasite surface is the merozoite surface protein-1 (MSP1). At red blood cell invasion MSP1 is proteolytically processed, and the 19-kDa C-terminal fragment (MSP119) remains on the surface and is taken into the red blood cell, where it is transferred to the food vacuole and persists until the end of the intracellular cycle. Because a number of specific antibodies inhibit erythrocyte invasion and parasite growth, MSP119 is therefore a promising target against malaria. Given the structural homology of cupredoxins with the Fab domain of monoclonal antibodies, an approach combining NMR and isothermal titration calorimetry (ITC) measurements with docking calculations based on BiGGER is employed on MSP119-cupredoxin complexes. Among the cupredoxins tested, rusticyanin forms a well defined complex with MSP119 at a site that overlaps with the surface recognized by the inhibitory antibodies. The addition of holo-rusticyanin to infected cells results in parasitemia inhibition, but negligible effects on parasite growth can be observed for apo-rusticyanin and other proteins of the cupredoxin family. These findings point to rusticyanin as an excellent therapeutic tool for malaria treatment and provide valuable information for drug design.

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 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.

Proteins on the surface of the malaria parasite and cell invasion

Parasitology ◽  
1994 ◽  
Vol 108 (S1) ◽  
pp. S5-S18 ◽  
Author(s):  
A. A. Holder
Keyword(s):  
Amino Acid ◽  
Cell Surface ◽  
Malaria Parasite ◽  
Surface Protein ◽  
Cell Types ◽  
Merozoite Surface Protein ◽  
Amino Acid Sequences ◽  
Specific Cell ◽  
Binding Studies ◽  
Erythrocyte Invasion

SUMMARYThe malaria parasite exists in an extracellular form at several stages in its life cycle. Within the vertebrate host, sporozoites and merozoites have to invade specific cell types. Proteins on the surface of the parasite or externalized from specialized organelles have been implicated as ligands for receptors on the host cell surface. Direct binding studies have identified parasite proteins that interact with the target cell surface. Examination of the deduced amino acid sequences has allowed the identification of primary structural motifs which may have roles in this process. On the sporozoite, the circum-sporozoite protein and sporozoite surface protein-2, a protein initially located within micronemes, have been found to contain an amino acid sequence thought to be involved in mediating recognition of sulphated polysaccharides on the surface of a liver cell. On the merozoite, merozoite surface protein-1 may be involved in the initial recognition of red blood cells; this protein undergoes a complex series of modifications in the time between its synthesis as a precursor molecule and successful erythrocyte invasion. Other merozoite proteins located at the apical end of the parasite have been identified as erythrocyte or reticulocyte binding proteins.

scholarly journals A Set of Glycosylphosphatidyl Inositol-Anchored Membrane Proteins of Plasmodium falciparum Is Refractory to Genetic Deletion

2006 ◽  
Vol 74 (7) ◽  
pp. 4330-4338 ◽  
Author(s):  
Paul R. Sanders ◽  
Lev M. Kats ◽  
Damien R. Drew ◽  
Rebecca A. O'Donnell ◽  
Matthew O'Neill ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Membrane Proteins ◽  
Surface Protein ◽  
Merozoite Surface Protein ◽  
Gene Encoding ◽  
Erythrocyte Invasion ◽  
Genes Encoding ◽  
Genetic Deletion ◽  
Invasion Pathway ◽  
Glycosylphosphatidyl Inositol

ABSTRACT Targeted gene disruption has proved to be a powerful approach for studying the function of important ligands involved in erythrocyte invasion by the extracellular merozoite form of the human malaria parasite, Plasmodium falciparum. Merozoite invasion proceeds via a number of seemingly independent alternate pathways, such that entry can proceed with parasites lacking particular ligand-receptor interactions. To date, most focus in this regard has been on single-pass (type 1) membrane proteins that reside in the secretory organelles. Another class of merozoite proteins likely to include ligands for erythrocyte receptors are the glycosylphosphatidyl inositol (GPI)-anchored membrane proteins that coat the parasite surface and/or reside in the apical organelles. Several of these are prominent vaccine candidates, although their functions remain unknown. Here, we systematically attempted to disrupt the genes encoding seven of the known GPI-anchored merozoite proteins of P. falciparum by using a double-crossover gene-targeting approach. Surprisingly, and in apparent contrast to other merozoite antigen classes, most of the genes (six of seven) encoding GPI-anchored merozoite proteins are refractory to genetic deletion, with the exception being the gene encoding merozoite surface protein 5 (MSP-5). No distinguishable growth rate or invasion pathway phenotype was detected for the msp-5 knockout line, although its presence as a surface-localized protein was confirmed.

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.

Sign in / Sign up

Export Citation Format

Share Document