The C-terminal 42-kDa region of Plasmodium falciparum Merozoite Surface Protein 1 (MSP-142) and its two proteolytic components, MSP-133 and MSP-119, are primary candidates for a malaria blood-stage vaccine. The long-term goal of the research proposed here is to advance understanding of the molecular and genetic basis of the evolution of human B and T-cell immunity to MSP-1 in high-transmission areas of Africa. Our recent observations indicate that: a) MSP-1[19]-specific invasion inhibitory antibodies (Ab) quantified using a novel approach that utilizes transgenic parasites differing only in their MSP-1[19] domain are a major component of the total invasion inhibitory activity of most adults living in high- or low-transmission areas of western Kenya. The level of these inhibitory Abs is predictive of the rate of re-infection in the low-transmission site, b) In the high-transmission area where infants are at risk of malaria morbidity, IgG Abs to MSP-1[19] and MSP-1[42] increase between 3 months and 4 years of age, c) Ab to the MSP-1[19] and MSP-1[42] prototypic MAD20 and K1 alleles are serologically cross-reactive, d) Abs to MSP-1[33] are rare, consistent with the notion that B cell epitopes are not located in this region of MSP-1[42]. In contrast, whereas T cell responses to the MSP-1[42] K1 allele are also uncommon, responses to the MSP-1[42] MAD20 allele and an epitope localized to the MSP-1[33] increase progressively between 0 to 14 years of age, indicating that unlike Ab responses T cell immunity to MSP-1 is allele-specific.
The specific aims will test the following hypotheses: 1) Genotypically diverse and repeated Pf blood-stage infections experienced by adulthood result in stable and high levels of functional invasion inhibitory Abs directed against both the MAD20 and K1 alleles of MSP-1[19]; 2) Memory CD4 + T cells (CD45RA-/CCR7+ and CD45RA-/CCR7-) directed against MSP-1[42] epitopes, particularly those contained within the MSP-1[33], develop after repeated infections with genetically diverse populations of Pf; 3) Infants acquire MSP-1[19] specific invasion inhibitory Ab according to their individual histories of prior Pf infections beating the corresponding genotype; 4) CD4 + T cells with surface markers indicative of a shift from naive to central memory and effector memory phenotypes (CD45RA+/CCR7+ -->CD45RA-/CCR7+ --> CD45RA-/CCR7-) develop by 24-36 months of age in infants. Study of these problems will advance fundamental knowledge of the molecular mechanisms by which anti-parasite and anti-disease responses are generated and maintained in humans who are repeated exposed to genetically complex populations of P. falciparum in malaria endemic areas. The data will also have practical implications for malaria vaccine studies.
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