The merozoite surface protein-1 (MSP-1) has become the most significant single candidate for a vaccine against the erythrocytic stages of malaria. Despite long-standing observations that parasite-derived MSP-1 protein could elicit protective host responses in both primate and rodent models of malaria, there has been limited information on the regions of the molecule required for protection and the mechanisms involved in this immunity. Our laboratory has been studying the MSP-1 protein from the rodent malarial parasite P. yoelii based on our earlier identification of a monoclonal antibody which had dramatic protective activity against a normally lethal challenge infection. We subsequently established that this antibody recognizes a discontinuous, disulfide-dependent epitope in the conserved, carboxyl-terminal region of the MSP-1 protein. Others have suggested that the cysteines in this region are arranged in two epidermal growth factor (EGF)-like domalns and have shown that it is retained on the merozoite surface after erythrocyte invasion. ObtaIning recombinant polypeptide which mimicked the structure of the carboxyl-terminal region of MSP-1 has proven to be difficult, presumably due to the requirement for proper disulfide pairing. However, in the previous granting period we have shown that the two EGF-like domains of the P. yoelli MSP-1 protein can be expressed in a native configuration when synthesized as a fusion protein with glutathione-S-transferase (GST). Moreover, we have shown that mice immunized with this antigen containing only 10kDa of plasmodial sequence can be almost completely protected against a normally lethal challenge infection. Our experiments to date support the role of serum antibodies in this protection. These findings have provided a model system for studying the immune response to a major erythrocytic-stage antigen of malaria parasites. We now propose a series of studies to investigate the variables surrounding the induction of protective immunity, to analyze in detail the serological responses induced with an emphasis on identification of protective antibodies, to examine the T-cell responses to epitopes derived from the MSP-1 molecule, and to begin to explore the structure and function of the carboxyl-terminal region of the protein. These findings may provide information relevant to the development of a successful vaccine against erythrocytic-stage infection and also illuminate the biological significance of the MSP-1 protein in the plasmodial life cycle.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI021089-10
Application #
2671790
Study Section
Microbial Physiology and Genetics Subcommittee 2 (MBC)
Project Start
1985-01-01
Project End
1998-11-10
Budget Start
1998-08-01
Budget End
1998-11-10
Support Year
10
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Allegheny University of Health Sciences
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19129
Rotman, H L; Daly, T M; Long, C A (1999) Plasmodium: immunization with carboxyl-terminal regions of MSP-1 protects against homologous but not heterologous blood-stage parasite challenge. Exp Parasitol 91:78-85
Kang, Y; Calvo, P A; Daly, T M et al. (1998) Comparison of humoral immune responses elicited by DNA and protein vaccines based on merozoite surface protein-1 from Plasmodium yoelii, a rodent malaria parasite. J Immunol 161:4211-9
Rotman, H L; Daly, T M; Clynes, R et al. (1998) Fc receptors are not required for antibody-mediated protection against lethal malaria challenge in a mouse model. J Immunol 161:1908-12
Daly, T M; Long, C A (1996) Influence of adjuvants on protection induced by a recombinant fusion protein against malarial infection. Infect Immun 64:2602-8
Calvo, P A; Daly, T M; Long, C A (1996) Plasmodium yoelii: the role of the individual epidermal growth factor-like domains of the merozoite surface protein-1 in protection from malaria. Exp Parasitol 82:54-64
Farley, P J; Long, C A (1995) Plasmodium yoelii yoelii 17XL MSP-1: fine-specificity mapping of a discontinuous, disulfide-dependent epitope recognized by a protective monoclonal antibody using expression PCR (E-PCR). Exp Parasitol 80:328-32
Kang, Y; Long, C A (1995) Sequence heterogeneity of the C-terminal, Cys-rich region of the merozoite surface protein-1 (MSP-1) in field samples of Plasmodium falciparum. Mol Biochem Parasitol 73:103-10
Daly, T M; Long, C A (1995) Humoral response to a carboxyl-terminal region of the merozoite surface protein-1 plays a predominant role in controlling blood-stage infection in rodent malaria. J Immunol 155:236-43
Farley, P J; Srivastava, R; Long, C A (1994) Sequence of the gene encoding the N-terminal portion of the Plasmodium yoelii yoelii 17XL merozoite surface protein-1 (MSP-1). Gene 151:335-6
Nussenzweig, R S; Long, C A (1994) Malaria vaccines: multiple targets. Science 265:1381-3

Showing the most recent 10 out of 20 publications