scholarly journals Immunization with a Combination of Merozoite Surface Proteins 4/5 and 1 Enhances Protection against Lethal Challenge with Plasmodium yoelii

2002 ◽  
Vol 70 (12) ◽  
pp. 6606-6613 ◽  
Author(s):  
Lukasz Kedzierski ◽  
Casilda G. Black ◽  
Matthew W. Goschnick ◽  
Anthony W. Stowers ◽  
Ross L. Coppel
Keyword(s):  
Protective Efficacy ◽  
Surface Protein ◽  
Merozoite Surface Protein ◽  
Plasmodium Yoelii ◽  
Surface Proteins ◽  
Lethal Challenge ◽  
Degree Of Protection ◽  
Multiple Components ◽  
Epidermal Growth ◽  
Stage Infection

ABSTRACT It is widely believed that subunit vaccines composed of multiple components will offer greater protection against challenge by malaria, and yet there is little experimental evidence to support this view. We set out to test this proposition in the Plasmodium yoelii challenge system in rodents by comparing the degree of protection conferred by immunization with a mixture of merozoite surface proteins to that conferred by single proteins. We therefore examined a defined protein mixture made of the epidermal growth factor-like domains of P. yoelli merozoite surface protein 1 (MSP1) and MSP4/5, the homologue of P. falciparum MSP4 and MSP5. In the present study we demonstrate that this combination of recombinant proteins dramatically enhances protection against lethal malaria challenge compared to either protein administered alone. Many mice immunized with the MSP4/5 plus MSP119 combination did not develop detectable parasitemia after challenge. Combined immunization with MSP119 and yMSP4/5, a product characterized by lower protective efficacy, also greatly enhanced protection by reducing peak parasitemias and increasing the numbers of survivors. In some combination trials, levels of antibodies to MSP119 were elevated compared to the MSP119 alone group; however, improved protection occurred regardless of whether boosting of the anti-MSP119 response was observed. Boosting of anti-MSP119 did not appear to be due to contaminating endotoxin in the EcMSP4/5 material since enhanced protection was observed in C3H/HeJ mice, which are endotoxin insensitive. Collectively, these experiments show that multiantigen combinations offer enhanced levels of protection against asexual stage infection and suggest that combinations of MSP1, MSP4, and MSP5 should be evaluated further for use in humans.

scholarly journals A Protective Glycosylphosphatidylinositol-Anchored Membrane Protein of Plasmodium yoelii Trophozoites and Merozoites Contains Two Epidermal Growth Factor-Like Domains

2000 ◽  
Vol 68 (11) ◽  
pp. 6189-6195 ◽  
Author(s):  
James M. Burns ◽  
Carla C. Belk ◽  
Patricia D. Dunn
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
High Titer ◽  
Rabbit Antiserum ◽  
Surface Protein ◽  
Merozoite Surface Protein ◽  
Plasmodium Yoelii ◽  
Surface Proteins ◽  
Reading Frame ◽  
Epidermal Growth

ABSTRACT Using sera from mice immunized and protected againstPlasmodium yoelii malaria, we identified a novel blood-stage antigen gene, pypag-2. The 2.1-kbpypag-2 cDNA contains a single open reading frame that encodes a 409-amino-acid protein with a predicted molecular mass of 46.8 kDa. Unlike many characterized plasmodial antigens, blocks of tandemly repeated amino acids are lacking in the pypAg-2 protein sequence. Recombinant pypAg-2, comprising the full-length protein minus the predicted N-terminal signal and C-terminal anchor sequences, was produced and used to raise a high-titer polyclonal rabbit antiserum. This antiserum was used to identify and characterize the native protein through immunoblotting, immunoprecipitation and immunofluorescence assays. Consistent with the presence of a glycosylphosphatidylinositol anchor, pypAg-2 fractionated with the detergent phase of Triton X-114-solubilized proteins and could be metabolically labeled with [3H]palmitic acid. By immunofluorescence, pypAg-2 expression was localized to both the trophozoite and merozoite membranes. Similar to Plasmodium falciparum merozoite surface protein 1, pypAg-2 contains two C-terminal epidermal growth factor (EGF)-like domains. Most importantly, immunization with recombinant pypAg-2 protected mice against lethal P. yoeliimalaria. Thus, pypAg-2 is a target of protective immune responses and represents a novel addition to the family of merozoite surface proteins that contain one or more EGF-like domains.

Comparison of the protective efficacy of yeast-derived and Escherichia coli-derived recombinant merozoite surface protein 4/5 against lethal challenge by Plasmodium yoelii

Vaccine ◽  
2001 ◽  
Vol 19 (32) ◽  
pp. 4661-4668 ◽  
Author(s):  
Lukasz Kedzierski ◽  
Casilda G Black ◽  
Anthony W Stowers ◽  
Matthew W Goschnick ◽  
David C Kaslow ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Protective Efficacy ◽  
Surface Protein ◽  
Merozoite Surface Protein ◽  
Plasmodium Yoelii ◽  
Lethal Challenge

scholarly journals Oral Immunization with a Combination of Plasmodium yoelii Merozoite Surface Proteins 1 and 4/5 Enhances Protection against Lethal Malaria Challenge

2004 ◽  
Vol 72 (10) ◽  
pp. 6172-6175 ◽  
Author(s):  
Lina Wang ◽  
Matthew W. Goschnick ◽  
Ross L. Coppel
Keyword(s):  
Escherichia Coli ◽  
Malaria Infection ◽  
Surface Protein ◽  
Merozoite Surface Protein ◽  
Oral Immunization ◽  
Plasmodium Yoelii ◽  
Antibody Responses ◽  
Surface Proteins ◽  
Merozoite Surface Protein 1

ABSTRACT Oral immunization of mice with Escherichia coli-expressed Plasmodium yoelii merozoite surface protein 4/5 or the C-terminal 19-kDa fragment of merozoite surface protein 1 induced systemic antibody responses and protected mice against lethal malaria infection. A combination of these two proteins administered orally conferred improved protection compared to that conferred by either protein administered alone.

scholarly journals A Common Cross-species Function for the Double Epidermal Growth Factor-like Modules of the Highly DivergentPlasmodiumSurface Proteins MSP-1 and MSP-8

2004 ◽  
Vol 279 (19) ◽  
pp. 20147-20153 ◽  
Author(s):  
Damien R. Drew ◽  
Rebecca A. O'Donnell ◽  
Brian J. Smith ◽  
Brendan S. Crabb
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Drug Targets ◽  
Point Mutations ◽  
Surface Protein ◽  
Merozoite Surface Protein ◽  
Surface Proteins ◽  
Parasite Line ◽  
Asexual Blood Stage ◽  
Epidermal Growth

An understanding of structural and functional constraints on the C-terminal double epidermal growth factor (EGF)-like modules of merozoite surface protein (MSP)-1 and related proteins is of importance to the development of these molecules as malaria vaccines and drug targets. Using allelic replacement, we show thatPlasmodium falciparumparasites can invade erythrocytes and grow efficiently in the absence of an MSP-1 protein with authentic MSP-1 EGF domains. In this mutant parasite line, the MSP-1 EGFs were replaced by the corresponding double EGF module fromP. bergheiMSP-8, the sequence of which shares only low identity with its MSP-1 counterpart. Hence, the C-terminal EGF domains of at least somePlasmodiumsurface proteins appear to perform the same function in asexual blood-stage development. Mapping the surface location of the few residues that are common to these functionally complementary EGF modules revealed the presence of a highly conserved pocket of potential functional significance. In contrast to MSP-8, an even more divergent double EGF module, that from the sexual stage protein PbS25, was not capable of complementing MSP-1 EGF function. More surprisingly, two chimeric double EGF modules comprising hybrids of the EGF domains fromP. falciparumandP. chabaudiMSP-1 were also not capable of replacing theP. falciparumMSP-1 EGF module. Together, these data suggest that although the MSP-1 EGFs can accommodate extensive sequence diversity, there appear to be constraints that may restrict the simple accumulation of point mutations in the face of immune pressure in the field.

scholarly journals Immunization with Recombinant Plasmodium yoelii Merozoite Surface Protein 4/5 Protects Mice against Lethal Challenge

2000 ◽  
Vol 68 (10) ◽  
pp. 6034-6037 ◽  
Author(s):  
Lukasz Kedzierski ◽  
Casilda G. Black ◽  
Ross L. Coppel
Keyword(s):  
Plasmodium Falciparum ◽  
Recombinant Protein ◽  
Subunit Vaccine ◽  
Surface Protein ◽  
Merozoite Surface Protein ◽  
Plasmodium Yoelii ◽  
Lethal Challenge ◽  
A Subunit ◽  
Peak Parasitemia ◽  
Antibody Levels

ABSTRACT Plasmodium yoelii merozoite surface protein 4/5 (PyMSP4/5), expressed as a recombinant protein, was highly effective at protecting mice against lethal challenge with P. yoelii. There was a significant correlation between prechallenge antibody levels and peak parasitemia, suggesting that the homologues of PyMSP4/5 in Plasmodium falciparum are promising components of a subunit vaccine against malaria.

scholarly journals Passive Immunization with Antibodies against Three Distinct Epitopes on Plasmodium yoelii Merozoite Surface Protein 1 Suppresses Parasitemia

1998 ◽  
Vol 66 (8) ◽  
pp. 3925-3930 ◽  
Author(s):  
Lilian M. Spencer Valero ◽  
Solabomi A. Ogun ◽  
Suzanne L. Fleck ◽  
Irene T. Ling ◽  
Terry J. Scott-Finnigan ◽  
...  
Keyword(s):  
Passive Immunization ◽  
Surface Protein ◽  
Merozoite Surface Protein ◽  
Plasmodium Yoelii ◽  
Blood Stage ◽  
Merozoite Surface Protein 1 ◽  
C Terminus ◽  
Epidermal Growth ◽  
Lethal Blood

ABSTRACT We have produced monoclonal antibodies against Plasmodium yoelii merozoite surface protein 1 (MSP-1) and have assessed their ability to suppress blood stage parasitemia by passive immunization. Six immunoglobulin G antibodies were characterized in detail: three (B6, D3, and F5) were effective in suppressing a lethal blood stage challenge infection, two (B10 and G3) were partially effective, and one (B4) was ineffective. MSP-1 is the precursor to a complex of polypeptides on the merozoite surface; all of the antibodies bound to this precursor and to an ∼42-kDa fragment (MSP-142) that is derived from the C terminus of MSP-1. MSP-142 is further cleaved to an N-terminal ∼33-kDa polypeptide (MSP-133) and a C-terminal ∼19-kDa polypeptide (MSP-119) comprised of two epidermal growth factor (EGF)-like modules. D3 reacted with MSP-142 but not with either of the constituents MSP-133 and MSP-119, B4 recognized an epitope within the N terminus of MSP-133, and B6, B10, F5, and G3 bound to MSP-119. B10 and G3 bound to epitopes that required both C-terminal EGF-like modules for their formation, whereas B6 and F5 bound to epitopes in the first EGF-like module. These results indicate that at least three distinct epitopes on P. yoelii MSP-1 are recognized by antibodies that suppress parasitemia in vivo.

Disruption of Plasmodium berghei merozoite surface protein 7 gene modulates parasite growth in vivo

Blood ◽  
2005 ◽  
Vol 105 (1) ◽  
pp. 394-396 ◽  
Author(s):  
Rita Tewari ◽  
Solabomi A. Ogun ◽  
Ruwani S. Gunaratne ◽  
Andrea Crisanti ◽  
Anthony A. Holder
Keyword(s):  
Plasmodium Falciparum ◽  
Gene Family ◽  
Plasmodium Berghei ◽  
Surface Protein ◽  
Merozoite Surface Protein ◽  
Plasmodium Yoelii ◽  
Parasite Growth ◽  
Surface Proteins ◽  
Rate Of Increase

Abstract Merozoite invasion of red blood cells is crucial to the development of the parasite that causes malaria. Merozoite surface proteins (MSPs) mediate the first interaction between parasite and erythrocyte. In Plasmodium falciparum, they include a complex of products from at least 3 genes (msp1, msp6, and msp7), one of which, msp7, is part of a gene family containing 3 and 6 adjacent members in Plasmodium yoelii and Plasmodium falciparum, respectively. We have identified and disrupted msp7 in the Plasmodium berghei gene family. The protein is expressed in schizonts and colocalizes with MSP1. The synthesis and processing of MSP1 was unaffected in the parasite with the disrupted gene (MSP7ko). Disruption of msp7 was not lethal but affected blood-stage parasite growth. MSP7ko parasites initially grew more slowly than wild-type parasites. However, when reticulocytes were prevalent, the rate of increase in parasitemia was similar, suggesting that MSP7ko parasites prefer to invade and grow within reticulocytes. (Blood. 2005;105:394-396)

scholarly journals Recombinant Mycobacterium bovis Bacillus Calmette-Guérin Secreting Merozoite Surface Protein 1 (MSP1) Induces Protection against Rodent Malaria Parasite Infection Depending on MSP1-stimulated Interferon γ and Parasite-specific Antibodies

1998 ◽  
Vol 188 (5) ◽  
pp. 845-854 ◽  
Author(s):  
Sohkichi Matsumoto ◽  
Hideharu Yukitake ◽  
Hiroji Kanbara ◽  
Takeshi Yamada
Keyword(s):  
Surface Protein ◽  
Merozoite Surface Protein ◽  
Interferon Γ ◽  
Secretory Protein ◽  
Plasmodium Yoelii ◽  
Parasite Infection ◽  
Bacillus Calmette Guerin ◽  
Degree Of Protection ◽  
Merozoite Surface Protein 1 ◽  
Ifn Γ

The merozoite surface protein 1 (MSP1) has emerged as a leading malaria vaccine candidate at the erythrocytic stage. Recombinant bacillus Calmette-Guérin (rBCG), which expressed a COOH-terminal 15-kD fragment of MSP1 of Plasmodium yoelii (MSP1-15) as a fusion protein with a secretory protein of Mycobacterium kansasii, was constructed. Immunization of mice with this rBCG induced a higher degree of protection against blood-stage parasite infection than with recombinant MSP1-15 in the RIBI adjuvant (RIBI ImmunoChem Research, Inc., Hamilton, MT) or incomplete Freund's adjuvant systems. We studied the mechanism of protection induced by MSP1-15, and found that interferon (IFN)-γ had a major role in protection in all adjuvant systems we examined. Mice that produced low amounts of MSP1-15 stimulated IFN-γ and could not control parasite infection. The antibody against MSP1-15 did not play a major role in protection in this system. After parasite infection, immunoglobulin G2a antibodies, which had been produced by IFN-γ stimulation, were induced and subsequently played an important role in eradicating parasites. Thus, both cellular and humoral immune responses were essential for protection from malaria disease. These data revealed that BCG is a powerful adjuvant to induce such a protective immune response against malaria parasites.

scholarly journals Merozoite Surface Protein 4/5 Provides Protection against Lethal Challenge with a Heterologous Malaria Parasite Strain

2004 ◽  
Vol 72 (10) ◽  
pp. 5840-5849 ◽  
Author(s):  
M. W. Goschnick ◽  
C. G. Black ◽  
L. Kedzierski ◽  
A. A. Holder ◽  
R. L. Coppel
Keyword(s):  
Surface Protein ◽  
Merozoite Surface Protein ◽  
Plasmodium Yoelii ◽  
Significant Protection ◽  
Parasite Strain ◽  
Gene Encoding ◽  
Lethal Challenge ◽  
Sequence Identity ◽  
Plasmodium Yoelii Yoelii ◽  
Heterologous Protection

ABSTRACT Immunization with merozoite surface protein 4/5 (MSP4/5), the murine malaria homologue of Plasmodium falciparum MSP4 and MSP5, has been shown to protect mice against challenge by parasites expressing the homologous form of the protein. The gene encoding MSP4/5 was sequenced from a number of Plasmodium yoelii isolates in order to assess the level of polymorphism in the protein. The gene was found to be highly conserved among the 13 P. yoelii isolates sequenced, even though many of the same isolates showed pronounced variability in their MSP119 sequences. Nonsynonymous mutations were detected only for the isolates Plasmodium yoelii nigeriensis N67 and Plasmodium yoelii killicki 193L and 194ZZ. Immunization and challenge of BALB/c mice showed that the heterologous MSP4/5 proteins were able to confer a level of protection against lethal Plasmodium yoelii yoelii YM challenge infection similar to that induced by immunization with the homologous MSP4/5 protein. To explore the limits of heterologous protection, mice were immunized with recombinant MSP4/5 protein from Plasmodium berghei ANKA and Plasmodium chabaudi adami DS and challenged with P. y. yoelii YM. Interestingly, significant protection was afforded by P. berghei ANKA MSP4/5, which shows 81% sequence identity with P. y. yoelii YM MSP4/5, but it was abolished upon reduction and alkylation. Significant protection was not observed for mice immunized with recombinant P. c. adami DS MSP4/5, which shows 55.7% sequence identity with P. y. yoelii YM MSP4/5. This study demonstrates the robustness of MSP4/5 in conferring protection against variant forms of the protein in a murine challenge system, in contrast to the situation found for other asexual-stage proteins, such as MSP119 and AMA1.

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