Passive Immunization with a Multicomponent Vaccine against Conserved Domains of Apical Membrane Antigen 1 and 235-Kilodalton Rhoptry Proteins Protects Mice against<i>Plasmodium yoelii</i>Blood-Stage Challenge Infection

Narum, David L.; Ogun, Solabomi A.; Batchelor, Adrian H.; Holder, Anthony A.

doi:10.1128/iai.00573-06

Cited by 26 publications

(30 citation statements)

References 58 publications

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“…It is documented that combinations of different parasite strains with different mouse strains give different susceptibility patterns of malaria (47) and that the protection depends on not only the immunity to a specific antigen but also various other factors such as diet (1). Our results with enolase are similar to those obtained with other malaria candidate antigens and P. yoelii lethal strain combinations (7,32,59). Specificity of enolase as an antigen and surface localization.…”

Section: Resultssupporting

confidence: 78%

Protective Properties and Surface Localization ofPlasmodium falciparumEnolase

et al. 2007

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The enolase protein of the human malarial parasite Plasmodium falciparum has recently been characterized. Apart from its glycolytic function, enolase has also been shown to possess antigenic properties and to be present on the cell wall of certain invasive organisms, such as Candida albicans. In order to assess whether enolase of P. falciparum is also antigenic, sera from residents of a region of Eastern India where malaria is endemic were tested against the recombinant P. falciparum enolase (r-Pfen) protein. About 96% of immune adult sera samples reacted with r-Pfen over and above the seronegative controls. Rabbit anti-r-Pfen antibodies inhibited the growth of in vitro cultures of P. falciparum. Mice immunized with r-Pfen showed protection against a challenge with the 17XL lethal strain of the mouse malarial parasite Plasmodium yoelii. The antibodies raised against r-Pfen were specific for Plasmodium and did not react to the host tissues. Immunofluorescence as well as electron microscopic examinations revealed localization of the enolase protein on the merozoite cell surface. These observations establish malaria enolase to be a potential protective antigen.Malaria continues to be a life-threatening infectious disease in the tropical world. Despite tremendous efforts to control the malaria epidemic, current prophylaxis and drug treatments are proving insufficient. The extensive spreading of drug-resistant Plasmodium strains as well as insecticide-resistant mosquitoes makes it urgent to develop an effective malaria vaccine. Long years of antigen identification and characterization have yielded many potential vaccine candidates, but developing an effective malaria vaccine has remained an incredibly difficult challenge (17). It has been observed that immunity to the disease develops gradually, after many attacks and over many years, in adults living in areas where malaria is endemic (2). The successful passive transfer of this immunity by injecting antibodies from malaria-immune persons to children susceptible to malaria has demonstrated that antibodies alone can trigger protection (5, 9, 58). These experiments have worked across geographical borders, as immunoglobulin G (IgG) from malaria-immune West Africans have cured East Africans as well as Thai malaria patients (5). The nature of this immunity is poorly understood at the molecular level. However, attempts have been made to identify antigens, the humoral response against which leads to protection. Seroepidemiological studies have identified several specific malarial blood-stage antigens including ring-infected erythrocyte surface antigen (10), apical membrane antigen (53), and PfP0, a conserved ribosomal protein (7,18,24), as protective antigens.Enolase has been reported to be present on the cell surface of several organisms (38). It is also considered to be a major immunostimulatory protein in the case of visceral leishmaniasis (19). Enolase has been demonstrated to play a protective role in Candida albicans infection (31, 41, 55). Recently, it has also been ...

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Section: Resultssupporting

confidence: 78%

Protective Properties and Surface Localization ofPlasmodium falciparumEnolase

et al. 2007

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“…PyP140/ RON4 appears to be present in both free and bound forms, and its association with AMA1 is therefore likely to be mediated by interaction with the ectodomain of AMA1. The structural basis of this interaction is unclear, but it is unlikely to include sequences that include the epitope of the AMA1-specific MAb 45B1 (19), since this antibody precipitates the PyAMA1/RON4 complex (20). The epitope for MAb 48F8 has been identified in this study in a region between the N-terminal repetitive sequence and the C-terminal cysteine-rich domain of PyP140/RON4; this region could be important in the interaction between PyP140/RON4 and AMA1 because MAb 48F8 appears to recognize free PyP140/RON4 and does not appear to precipitate the complex (20).…”

Section: Discussionmentioning

confidence: 99%

“…The cloned rodent parasite P. yoelii yoelii YM (29) was obtained from David Walliker, University of Edinburgh, and grown in BALB/c mice. Slides were prepared with thin smears of blood parasitized with P. yoelii YM as described previously (19). For challenge infections, infected erythrocytes were collected into phosphate-buffered saline (PBS)-heparin.…”

Section: Methodsmentioning

confidence: 99%

Identification and Characterization of the Plasmodium yoelii PyP140/RON4 Protein, an Orthologue of Toxoplasma gondii RON4, Whose Cysteine-Rich Domain Does Not Protect against Lethal Parasite Challenge Infection

Narum¹,

Nguyen²,

Zhang³

et al. 2008

Infect Immun

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Previously, we identified a Plasmodium yoelii YM 140-kDa merozoite protein, designated PyP140, which formed a complex with apical membrane antigen 1 (AMA1). Furthermore, we produced a nonprotective monoclonal antibody (MAb), 48F8, that immunoprecipitated metabolically labeled PyP140 and localized the protein to the merozoite's apical end and, less frequently, to the merozoite surface, as observed by immunofluorescence assay (IFA). Here, using MAb 48F8, we have identified the pyp140 gene by screening a P. yoelii -Zap cDNA expression library. The pyp140 cDNA covers approximately 90% of the putative open reading frame (ORF) of PY02159 from the P. yoelii NL genome sequencing project. Analysis of the complete gene identified the presence of two introns. The ORF encodes a 102,407-Da protein with an amino-terminal signal sequence, a series of three unique types of repeats, and a cysteine-rich region. The binding site of MAb 48F8 was also identified. A BLAST search with the deduced amino acid sequence shows significant similarity with the Toxoplasma gondii RON4 protein and the Plasmodium falciparum RON4 protein, and the sequence is highly conserved in other Plasmodium species. We produced the cysteine-rich domain of PyP140/RON4 by using the Pichia pastoris expression system and characterized the recombinant protein biochemically and biophysically. BALB/c mice immunized with the protein formulated in oil-in-water adjuvants produced antibodies that recognize parasitized erythrocytes by IFA and native PyP140/RON4 by immunoblotting but failed to protect against a lethal P. yoelii YM infection. Our results show that PyP140/RON4 is located within the rhoptries or micronemes. It may associate in part with AMA1, but the conserved cysteine-rich domain does not appear to elicit inhibitory antibodies, a finding that is supported by the marked sequence conservation in this protein within Plasmodium spp., suggesting that it is not under immune pressure.

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“…The potential of AMA1 as a malaria vaccine candidate has been demonstrated in rodent models of malaria with both strain-specific [87][88][89] and cross-protective [90] protection observed. High levels of polymorphism in AMA1 [8,91,92] due to strong balancing selection [93] has resulted in hundreds of distinct AMA1 haplotypes; this might indicate that the development of a broadly effective AMA1-based malaria vaccine will be difficult.…”

Section: Apical Membrane Antigen 1 (Ama1)mentioning

confidence: 99%