Strain-specific immunity may drive adaptive polymorphism in the merozoite surface protein 1 of the rodent malaria parasite Plasmodium chabaudi.
ABSTRACT Clinical immunity against malaria is slow to develop, poorly understood and strongly strain-specific. Understanding how strain-specific immunity develops and identifying the parasite antigens involved is crucial to developing effective vaccines against the disease. In previous experiments we have shown that strain-specific protective immunity (SSPI) exists between genetically distinct strains (cloned lines) of the rodent malaria parasite Plasmodium chabaudi chabaudi in mice [Cheesman, S., Raza, A., Carter, R., 2006. Mixed strain infections and strain-specific protective immunity in the rodent malaria parasite P. chabaudi chabaudi in mice. Infect. Immun. 74, 2996-3001]. In two subsequent studies, we identified the highly polymorphic Merozoite Surface Protein 1 (MSP-1) as being the principal candidate molecule for the control of SSPI against P. c. chabaudi malaria [Martinelli et al., 2005; Pattaradilokrat, S., Cheesman, S.J., Carter R., 2007. Linkage group selection: towards identifying genes controlling strain-specific protective immunity in malaria. PLoS ONE 2(9):e857]. In the present study, we sequenced the whole msp1 gene of several genetically distinct strains of P. chabaudi and found high levels of genetic diversity. Protein sequence alignments reveal extensive allelic polymorphism between the P. chabaudi strains, concentrated primarily within five regions of the protein. The 3'-end sequence region, encoding the C-terminal 21 kDa region (MSP-1(21)), which is analogous and homologous to MSP-1(19) of Plasmodium falciparum, appears to have been subject to balancing selection. We have found that the strains with the lowest sequence identity at MSP-1(21) (i.e. AS/CB and AJ/CB) induce robust and reciprocal SSPI in experimental mice. In contrast, two strains that do not induce reciprocal SSPI are identical at the 21 kDa region. Final identification of the region(s) controlling SSPI will provide important information to help guide decisions about MSP-1 based vaccines.
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ABSTRACT: We evaluated repeated blood-stage infections with Plasmodium falciparum in eight Aotus lemurinus lemurinus monkeys. Over the course of seven infections with 10(4) P. falciparum (the Vietnam Oak Knoll [FVO] strain), the pre-patent period lengthened from 8.2 to 30.8 days; the peak parasitemia decreased from 4.5 x 10(5) to 0 parasites/microl (Challenges 6 and 7), and the requirement for treatment decreased from 100% to 0% (Challenges 3 to 7). Five weeks after the seventh FVO challenge, the eight immune and three naïve monkeys received 10(4) parasitized erythrocytes infected with P. falciparum (CAMP strain). The three control animals experienced uncontrolled parasitemias reaching between 4.8 and 7.7 x 10(5) parasites/microl (pre-patency = 6.3 days) and all required drug treatment; six of the eight immune monkeys became parasitemic (pre-patency = 8.8 days), but self-cured. Two of three of the monkeys having the greatest reductions in hematocrit (50-60%) also had the highest parasitemias (approximately 10(4) parasites/microl) before self-curing. Repeated homologous infections induced sterile immunity to homologous challenge; during heterologous challenge the monkeys developed clinically relevant, but not life-threatening, parasitemias and anemia.The American journal of tropical medicine and hygiene 07/2000; 62(6):675-80. · 2.53 Impact Factor
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ABSTRACT: Proteins often differ in amino-acid sequence across species. This difference has evolved by the accumulation of neutral mutations by random drift, the fixation of adaptive mutations by selection, or a mixture of the two. Here we propose a simple statistical test of the neutral protein evolution hypothesis based on a comparison of the number of amino-acid replacement substitutions to synonymous substitutions in the coding region of a locus. If the observed substitutions are neutral, the ratio of replacement to synonymous fixed differences between species should be the same as the ratio of replacement to synonymous polymorphisms within species. DNA sequence data on the Adh locus (encoding alcohol dehydrogenase, EC 18.104.22.168) in three species in the Drosophila melanogaster species subgroup do not fit this expectation; instead, there are more fixed replacement differences between species than expected. We suggest that these excess replacement substitutions result from adaptive fixation of selectively advantageous mutations.Nature 07/1991; 351(6328):652-4. · 38.60 Impact Factor