PfCP-2.9疟疾疫苗候选抗原系列突变体的构建及其表位和免疫学分析
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摘要
疟疾仍然严重威胁着人类的健康。世界卫生组织在2008年的疟疾报告中指出,2006年全世界大约有247,000,000人感染疟疾,其中约1,000,000人死亡；并且,死亡患者大多数是撒哈拉沙漠以南非洲地区的五岁以下儿童。随着疟原虫抗药性和蚊媒抗杀虫剂的出现和扩散,研发安全有效的疟疾疫苗已经成为未来疟疾防治的一种潜在的重要手段。
恶性疟原虫融合抗原-2.9(Plasmodium falciparum chimeric protein-2.9, PfCP-2.9)是由恶性疟原虫裂殖子表面蛋白1(Merozoite surface protein 1, MSP1)的C末端19kDa片段(PfMSPl-19)和恶性疟原虫顶端膜抗原-1(Apical membrane antigen-1, AMA-1)的Ⅲ亚区(PfAMA-1 (III))通过一段28个氨基酸的连接序列融合而成。在动物实验中,该融合抗原比其两个单组分具有更强的免疫原性和更高的体外抑制疟原虫生长效力。该疫苗的临床试验结果也表明,疫苗安全、耐受性好,并且具有较强的免疫原性。为探索该疫苗增强免疫应答的机制,我们利用定点突变的方式,采用Western Blot和酶联免疫吸附试验(Enzyme-linked immunosorbent assay, ELISA)相结合的检测方法分析该疫苗抗原的表位分布及其可能的功能。
为了解PfCP-2.9的表位分布,我们共设计了该抗原的17个单氨基酸突变体。这些突变位点有9个位于AMA-1 (III)组分,8个位于MSP1-19组分。AMA-1 (III)组分上的突变位点主要选择疟原虫种间高度保守的氨基酸位点,或者被单抗FS.12.19识别的氨基酸位点。该单抗虽然没有体外抑制活性,但是参与了不同疟原虫种间的交叉反应,而这种交叉反应被认为是抑制疟原虫入侵红细胞的机理之一。MSP1-19组分上的突变位点主要选择该抗原上已被确认的阻遏性位点,或者是在晶体结构中暴露于分子表面并且极有可能参与阻遏性或者抑制性表位形成的氨基酸位点。按照上述所设计的突变位点,我们采用重叠延伸聚合酶链反应(Overlap-extention Polymerase Chain Reaction)的方法,对pfcp-2.9基因分别进行定点突变。具体方法是：采用通用引物和相互重叠的两条突变引物中的一条,分别扩增出上、下游含突变位点的片段,再通过第二轮PCR,以纯化后的上、下游片段为模板,以两端的两条通用引物为引物,扩增产生突变体基因。将各突变体基因通过酶切,克隆到表达载体pPIC9K上,转化毕氏酵母(GS115),经过G418筛选后,在毕赤酵母中进行了分泌表达。在采用SDS-PAGE及Western Blot进行表达产物的检测中(以兔抗-PfCP-2.9为一抗),17个突变体基因均能在该表达系统中稳定表达出完整的蛋白,并能与PfCP-2.9免疫血清反应。这为进一步鉴定PfCP-2.9的表位分析提供了基础。
本实验室已制备了一组(共12株)PfCP-2.9的单克隆抗体。此外,从其它实验室获得一株单抗。这些单抗识别PfCP-2.9抗原的不同表位,具有不同的生物学特性和功能,包括识别线性表位或构象表位、具有抑制疟原虫入侵或阻遏该抑制作用等。采用Western Blot和ELISA方法,通过检测各单抗与各PfCP-2.9突变体的结合反应,分析这些单抗识别的表位及其分布。结果显示：(1)一株抑制性单抗mAb7G识别的表位与三个氨基酸位点突变(M62:Phe491→Ala, M82:Glu511→Gln和M84：Arg513→Lys)相关,这三个位点均位于AMA-1(Ⅲ)的C末端非结构区(Unstructured region)的分子表面,在空间构象上彼此靠近,并且其中的任何一个位点发生突变都会使mAb7G的识别明显减弱。(2)M62和M82的突变还致使单抗mAb11.12的结合发生减弱；M62使单抗mAbW9.10的结合减弱。这些结果提示,mAb11.12(Phe491和Glu511)和mAbW9.10 (Phe491)有可能通过结合位点的相互竞争而阻断mAb7G抗体的抑制活性；(3)在针对PfMSP1-19组分的突变体设计中,有四个突变体是针对MSP1-19阻遏性表位的突变,这些突变所在的位点分别是Asn15, Glu27, Leu31和Glu43,文献报道结果表明,这四个位点的突变可以阻断四个阻遏性单抗(mAb7.5, mAb2.2,mAb1E1和mAb111.4)与PfMSPl-19结合。本实验结果显示,采用Western Blot和ELISA方法均证实,阻遏性单抗mAblEl与PfCP-2.9上述位点的突变体结合与PfMSP1-19结果一致；(4)M160突变导致对多数单抗的结合发生改变,表明该位点(Asn15)可能在PfCP-2.9分子的折叠和维持构象中发挥重要作用。
为分析疟疾病人免疫血清与PfCP-2.9及其突变体的结合反应,我们收集了96份恶性疟疾病人的血清,采用ELISA方法检测这些血清样本对PfCP-2.9的识别情况。结果显示,其中91份血清识别PfCP-2.9,阳性率94.8%,表明在自然感染情况下,能产生针对PfCP-2.9疫苗抗原的特异抗体。在此基础上,我们选取其中74份阳性血清样本,比较它们与PfCP-2.9及其突变体的结合差异。结果显示,现场血清可以与大部分PfCP-2.9的突变体正常结合。但在PfMSPl-19组分上的突变体与血清结合发生了明显的改变,特别是突变其阻遏性表位的突变体(M160、M172、M176和M188),这可能缘于病人血清中存在较高水平的阻遏性抗体。这些结果为今后设计排除阻遏性表位的疫苗提供了依据。
为了解PfCP-2.9突变体的免疫原性及其免疫血清体外抑制疟原虫生长的效力是否发生改变,我们将PfCP-2.9及其三个突变阻遏性表位的突变体进行发酵和蛋白纯化,获得的重组蛋白进行平行新西兰兔免疫实验。免疫血清分析结果表明,PfCP-2.9与其突变体的免疫原性,即抗体水平,无显著差异(p>0.05)。我们分离了免疫兔血清中的总IgG并进行体外抑制试验。结果表明,PfCP-2.9免疫组与突变体免疫组的免疫血清及总IgG,在体外抑制疟原虫生长效力方面无统计学差异(p>0.05)。
小结：为分析PfCP-2.9疟疾疫苗候选抗原的表位及其生物学功能,我们采用重叠延伸聚合酶链反应的方法,对pfcp-2.9基因进行系列突变,制备了17个单氨基酸改变的PfCP-2.9突变体。利用本实验室前期制备的一组识别PfCP-2.9的单抗,采用Western Blot和ELISA的免疫学方法,分析单抗与突变体之间的识别反应,发现其中一些具有不同功能的单抗,其识别反应发生了改变；同时提出了其可能的生物学意义。此外,通过PfCP-2.9突变体与自然感染疟疾病人血清进行识别反应,发现其中一些突变体的识别反应发生了改变。以上结果,为阐明PfCP-2.9这个重要疟疾疫苗候选抗原的免疫保护机制,改进和设计更为有效的疟疾疫苗提供了依据和见解。
Malaria remains to be a severe tropical disease. It is reported by World Health Organization that it caused more than 247 million cases around the world and about 1 million death in 2006, most of which were in children under five years of age in Sub-Saharan Africa. With the emergence and spread of insecticide-resistant mosquitoes and drug-resistant parasites, there is an urgent need for the development of a safe and effective vaccine to prevent or even to eradicate the disease.
In a previous study, plasmodium falciparum chimeric protein-2.9 (PfCP-2.9) was constructed by fusing the C terminal 19kDa frangment (MSP1-19) of merozoite surface protein 1(MSP1) with apical membrane antigen-1 (AMA-1) domain III (AMA-1 (III)) through a 28-mer peptide. In animal studies, the chimeric protein was proved to enhance the immunogenicity, and in vitro growth inhibitory activities. Two separate Phase I clinical trials have also demonstrated that the vaccine candidate was safe, tolerable and immunogenic. In order to investigate the enhancement of the immunological mechanism, by which the vaccine exerts function, we performed an epitope mapping of PfCP-2.9 by Western Blot and enzyme-linked immunosorbent assays (ELISA).
In this study, we designed and created 17 mutants of PfCP-2.9 with single amino acid substitution. Nine of them were mutated on the AMA-1 (III) component, and the rest eight were made on the MSP 1-19 component. The mutated amino acids selected on AMA-1 (III) component are those highly conserved in the Plasmodium or involved in the formation of the epitope recognized by mAbF8.12.19, which was not inhibitory but involved in cross-reactivities across species. The eight aminio acid substitutions on MSP1-19 component were those proved to be involved in the formation of blocking epitopes or those surface-exposed on the crystal structure of PfMSPl-19 and putatively involved in the inhibitory or blocking epitopes. The above mutations were made by the method of overlap extention polymerase chain reaction (PCR), which generate the upstream or downstream fragments through the first round of PCR using the forward universial primer and a reverse mutant primer or the reverse universial primer and a forward mutant primer, respectively; and then combine the purified upstream and downstream fragments with the forward and reverse universial primes by the second round of PCR.The mutant genes were subsequently ligased into the expression vector of pPIC9K and sequenced. The vector with the correct target sequence was further transformed into the Pichia pastoris expression system to secrete the mutated proteins in the supernatant. By sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and Western Blot analysis, it was confirmed that all the 17 mutant genes were sucdessfully expressed and the mutant proteins could be recognized by the rabbit immune sera. These results provided bases for the investigation into the epitopes of PfCP-2.9.
The epitope mapping was carried out by Western Blot and ELISA, using the above mutant proteins as well as a serial of mAbs, which were prepared and characterized in our previous work or obtained from other labs. The results we obtained may have the following implications:(i) An inhibitory epitope recognized by mAb7G was found, and the epitope is closely related with three substitutions (M62:Phe491→Ala, M82:Glu511→Gln and M84:Arg513->Lys), because any of them could reduce the binding of the mAb. In addition, all of the three amino acids are in close proximity to each other in conformation on the C terminal unstructured region of AMA-1(Ⅲ). (ii) M62 and M82 could further reduce the binding of mAbG 11.12, while M62 could reduce the binding of mAbW9.10. Therefore, there is possibility that the two mAbs compete with mAb7G at the position of M62 and M82 and at the position of M62, separately. (iii) Some information about blocking epitopes was also obtained. There are four definitive amino acids (Asn15, Glu27, Leu31 and Glu43) that were involved in the formation of blocking epitopes on PfMSPl-19. It was reported that mutation of these four amino acids abolished the binding of blocking mAbs of mAb7.5, mAb2.2, mAb1E1 and mAb111.4, seperately. In this study, it was confirmed that the epitope recognized by mAb1E1 was the same as that identified on the PfMSP1-19 molecule. (iv) The amino acid of Asn15 was found to be of critical importance, since the substitution of this residue to Arg on PfCP-2.9 reduced the binding of most mAbs.
To investigate the recognition differences of sera from malaria infected individuals between PfCP-2.9 and its mutant proteins, we collected 96 sera samples from patients infected with Plasmodium falciparum. The results showed that 91 out of the 96 (94.8%) sera samples recognized PfCP-2.9, which indicated that anti-PfCP-2.9 specific antibodies could be produced during natural infections.74 positive sera samples were futher selected to compare the recognition between PfCP-2.9 and the mutant proteins. And the results showed that most of the mutant proteins could be recognized by the selected sera. However, apparent differences were found between PfCP-2.9 and the mutant proteins with substitutions on the MSP1-19 component (especially the mutations on blocking epitopes of PfMSP1-19), which implied that blocking antibodies dominate these sera samples. These results provide evidence for future vaccines eliminating blocking epitopes.
To investigate the immunogenicity of the mutant proteins, we performed animal studies in New Zealand White rabbits with Pichia expressed and purified PfCP-2.9 as well as three mutant proteins with substitution on blocking epitopes. The analysis from the rabbit immue sera showed that there were no significant differences between PfCP-2.9 and mutatated proteins, either in the ELISA titers (p>0.05) or in the in vitro growth inhibiton assay (GIA) by sera, as well as total IgG (p>0.05).
Briefly, in this study, we created a panel of 17 mutant proteins of PfCP-2.9 with single amino acid substitution. With the mAbs against PfCP-2.9 prepared in previous work, we have mapped some epitopes of the vaccine candidate by Western Blot and ELISA, and raised the possible biological function of these epitopes. Recognition of the mutant proteins by sera from natural infections was also investigated, and the results showed that the binding of some mutant proteins was altered by the sera samples, compared with the binding of the wild-type protein. The data obtained may prove to be valuable and helpful for designing more effective malaria vaccines against blood-stage parasites in future studies.
恶性疟原虫融合抗原-2.9(Plasmodium falciparum chimeric protein-2.9, PfCP-2.9)是由恶性疟原虫裂殖子表面蛋白1(Merozoite surface protein 1, MSP1)的C末端19kDa片段(PfMSPl-19)和恶性疟原虫顶端膜抗原-1(Apical membrane antigen-1, AMA-1)的Ⅲ亚区(PfAMA-1 (III))通过一段28个氨基酸的连接序列融合而成。在动物实验中,该融合抗原比其两个单组分具有更强的免疫原性和更高的体外抑制疟原虫生长效力。该疫苗的临床试验结果也表明,疫苗安全、耐受性好,并且具有较强的免疫原性。为探索该疫苗增强免疫应答的机制,我们利用定点突变的方式,采用Western Blot和酶联免疫吸附试验(Enzyme-linked immunosorbent assay, ELISA)相结合的检测方法分析该疫苗抗原的表位分布及其可能的功能。
为了解PfCP-2.9的表位分布,我们共设计了该抗原的17个单氨基酸突变体。这些突变位点有9个位于AMA-1 (III)组分,8个位于MSP1-19组分。AMA-1 (III)组分上的突变位点主要选择疟原虫种间高度保守的氨基酸位点,或者被单抗FS.12.19识别的氨基酸位点。该单抗虽然没有体外抑制活性,但是参与了不同疟原虫种间的交叉反应,而这种交叉反应被认为是抑制疟原虫入侵红细胞的机理之一。MSP1-19组分上的突变位点主要选择该抗原上已被确认的阻遏性位点,或者是在晶体结构中暴露于分子表面并且极有可能参与阻遏性或者抑制性表位形成的氨基酸位点。按照上述所设计的突变位点,我们采用重叠延伸聚合酶链反应(Overlap-extention Polymerase Chain Reaction)的方法,对pfcp-2.9基因分别进行定点突变。具体方法是：采用通用引物和相互重叠的两条突变引物中的一条,分别扩增出上、下游含突变位点的片段,再通过第二轮PCR,以纯化后的上、下游片段为模板,以两端的两条通用引物为引物,扩增产生突变体基因。将各突变体基因通过酶切,克隆到表达载体pPIC9K上,转化毕氏酵母(GS115),经过G418筛选后,在毕赤酵母中进行了分泌表达。在采用SDS-PAGE及Western Blot进行表达产物的检测中(以兔抗-PfCP-2.9为一抗),17个突变体基因均能在该表达系统中稳定表达出完整的蛋白,并能与PfCP-2.9免疫血清反应。这为进一步鉴定PfCP-2.9的表位分析提供了基础。
本实验室已制备了一组(共12株)PfCP-2.9的单克隆抗体。此外,从其它实验室获得一株单抗。这些单抗识别PfCP-2.9抗原的不同表位,具有不同的生物学特性和功能,包括识别线性表位或构象表位、具有抑制疟原虫入侵或阻遏该抑制作用等。采用Western Blot和ELISA方法,通过检测各单抗与各PfCP-2.9突变体的结合反应,分析这些单抗识别的表位及其分布。结果显示：(1)一株抑制性单抗mAb7G识别的表位与三个氨基酸位点突变(M62:Phe491→Ala, M82:Glu511→Gln和M84：Arg513→Lys)相关,这三个位点均位于AMA-1(Ⅲ)的C末端非结构区(Unstructured region)的分子表面,在空间构象上彼此靠近,并且其中的任何一个位点发生突变都会使mAb7G的识别明显减弱。(2)M62和M82的突变还致使单抗mAb11.12的结合发生减弱；M62使单抗mAbW9.10的结合减弱。这些结果提示,mAb11.12(Phe491和Glu511)和mAbW9.10 (Phe491)有可能通过结合位点的相互竞争而阻断mAb7G抗体的抑制活性；(3)在针对PfMSP1-19组分的突变体设计中,有四个突变体是针对MSP1-19阻遏性表位的突变,这些突变所在的位点分别是Asn15, Glu27, Leu31和Glu43,文献报道结果表明,这四个位点的突变可以阻断四个阻遏性单抗(mAb7.5, mAb2.2,mAb1E1和mAb111.4)与PfMSPl-19结合。本实验结果显示,采用Western Blot和ELISA方法均证实,阻遏性单抗mAblEl与PfCP-2.9上述位点的突变体结合与PfMSP1-19结果一致；(4)M160突变导致对多数单抗的结合发生改变,表明该位点(Asn15)可能在PfCP-2.9分子的折叠和维持构象中发挥重要作用。
为分析疟疾病人免疫血清与PfCP-2.9及其突变体的结合反应,我们收集了96份恶性疟疾病人的血清,采用ELISA方法检测这些血清样本对PfCP-2.9的识别情况。结果显示,其中91份血清识别PfCP-2.9,阳性率94.8%,表明在自然感染情况下,能产生针对PfCP-2.9疫苗抗原的特异抗体。在此基础上,我们选取其中74份阳性血清样本,比较它们与PfCP-2.9及其突变体的结合差异。结果显示,现场血清可以与大部分PfCP-2.9的突变体正常结合。但在PfMSPl-19组分上的突变体与血清结合发生了明显的改变,特别是突变其阻遏性表位的突变体(M160、M172、M176和M188),这可能缘于病人血清中存在较高水平的阻遏性抗体。这些结果为今后设计排除阻遏性表位的疫苗提供了依据。
为了解PfCP-2.9突变体的免疫原性及其免疫血清体外抑制疟原虫生长的效力是否发生改变,我们将PfCP-2.9及其三个突变阻遏性表位的突变体进行发酵和蛋白纯化,获得的重组蛋白进行平行新西兰兔免疫实验。免疫血清分析结果表明,PfCP-2.9与其突变体的免疫原性,即抗体水平,无显著差异(p>0.05)。我们分离了免疫兔血清中的总IgG并进行体外抑制试验。结果表明,PfCP-2.9免疫组与突变体免疫组的免疫血清及总IgG,在体外抑制疟原虫生长效力方面无统计学差异(p>0.05)。
小结：为分析PfCP-2.9疟疾疫苗候选抗原的表位及其生物学功能,我们采用重叠延伸聚合酶链反应的方法,对pfcp-2.9基因进行系列突变,制备了17个单氨基酸改变的PfCP-2.9突变体。利用本实验室前期制备的一组识别PfCP-2.9的单抗,采用Western Blot和ELISA的免疫学方法,分析单抗与突变体之间的识别反应,发现其中一些具有不同功能的单抗,其识别反应发生了改变；同时提出了其可能的生物学意义。此外,通过PfCP-2.9突变体与自然感染疟疾病人血清进行识别反应,发现其中一些突变体的识别反应发生了改变。以上结果,为阐明PfCP-2.9这个重要疟疾疫苗候选抗原的免疫保护机制,改进和设计更为有效的疟疾疫苗提供了依据和见解。
Malaria remains to be a severe tropical disease. It is reported by World Health Organization that it caused more than 247 million cases around the world and about 1 million death in 2006, most of which were in children under five years of age in Sub-Saharan Africa. With the emergence and spread of insecticide-resistant mosquitoes and drug-resistant parasites, there is an urgent need for the development of a safe and effective vaccine to prevent or even to eradicate the disease.
In a previous study, plasmodium falciparum chimeric protein-2.9 (PfCP-2.9) was constructed by fusing the C terminal 19kDa frangment (MSP1-19) of merozoite surface protein 1(MSP1) with apical membrane antigen-1 (AMA-1) domain III (AMA-1 (III)) through a 28-mer peptide. In animal studies, the chimeric protein was proved to enhance the immunogenicity, and in vitro growth inhibitory activities. Two separate Phase I clinical trials have also demonstrated that the vaccine candidate was safe, tolerable and immunogenic. In order to investigate the enhancement of the immunological mechanism, by which the vaccine exerts function, we performed an epitope mapping of PfCP-2.9 by Western Blot and enzyme-linked immunosorbent assays (ELISA).
In this study, we designed and created 17 mutants of PfCP-2.9 with single amino acid substitution. Nine of them were mutated on the AMA-1 (III) component, and the rest eight were made on the MSP 1-19 component. The mutated amino acids selected on AMA-1 (III) component are those highly conserved in the Plasmodium or involved in the formation of the epitope recognized by mAbF8.12.19, which was not inhibitory but involved in cross-reactivities across species. The eight aminio acid substitutions on MSP1-19 component were those proved to be involved in the formation of blocking epitopes or those surface-exposed on the crystal structure of PfMSPl-19 and putatively involved in the inhibitory or blocking epitopes. The above mutations were made by the method of overlap extention polymerase chain reaction (PCR), which generate the upstream or downstream fragments through the first round of PCR using the forward universial primer and a reverse mutant primer or the reverse universial primer and a forward mutant primer, respectively; and then combine the purified upstream and downstream fragments with the forward and reverse universial primes by the second round of PCR.The mutant genes were subsequently ligased into the expression vector of pPIC9K and sequenced. The vector with the correct target sequence was further transformed into the Pichia pastoris expression system to secrete the mutated proteins in the supernatant. By sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and Western Blot analysis, it was confirmed that all the 17 mutant genes were sucdessfully expressed and the mutant proteins could be recognized by the rabbit immune sera. These results provided bases for the investigation into the epitopes of PfCP-2.9.
The epitope mapping was carried out by Western Blot and ELISA, using the above mutant proteins as well as a serial of mAbs, which were prepared and characterized in our previous work or obtained from other labs. The results we obtained may have the following implications:(i) An inhibitory epitope recognized by mAb7G was found, and the epitope is closely related with three substitutions (M62:Phe491→Ala, M82:Glu511→Gln and M84:Arg513->Lys), because any of them could reduce the binding of the mAb. In addition, all of the three amino acids are in close proximity to each other in conformation on the C terminal unstructured region of AMA-1(Ⅲ). (ii) M62 and M82 could further reduce the binding of mAbG 11.12, while M62 could reduce the binding of mAbW9.10. Therefore, there is possibility that the two mAbs compete with mAb7G at the position of M62 and M82 and at the position of M62, separately. (iii) Some information about blocking epitopes was also obtained. There are four definitive amino acids (Asn15, Glu27, Leu31 and Glu43) that were involved in the formation of blocking epitopes on PfMSPl-19. It was reported that mutation of these four amino acids abolished the binding of blocking mAbs of mAb7.5, mAb2.2, mAb1E1 and mAb111.4, seperately. In this study, it was confirmed that the epitope recognized by mAb1E1 was the same as that identified on the PfMSP1-19 molecule. (iv) The amino acid of Asn15 was found to be of critical importance, since the substitution of this residue to Arg on PfCP-2.9 reduced the binding of most mAbs.
To investigate the recognition differences of sera from malaria infected individuals between PfCP-2.9 and its mutant proteins, we collected 96 sera samples from patients infected with Plasmodium falciparum. The results showed that 91 out of the 96 (94.8%) sera samples recognized PfCP-2.9, which indicated that anti-PfCP-2.9 specific antibodies could be produced during natural infections.74 positive sera samples were futher selected to compare the recognition between PfCP-2.9 and the mutant proteins. And the results showed that most of the mutant proteins could be recognized by the selected sera. However, apparent differences were found between PfCP-2.9 and the mutant proteins with substitutions on the MSP1-19 component (especially the mutations on blocking epitopes of PfMSP1-19), which implied that blocking antibodies dominate these sera samples. These results provide evidence for future vaccines eliminating blocking epitopes.
To investigate the immunogenicity of the mutant proteins, we performed animal studies in New Zealand White rabbits with Pichia expressed and purified PfCP-2.9 as well as three mutant proteins with substitution on blocking epitopes. The analysis from the rabbit immue sera showed that there were no significant differences between PfCP-2.9 and mutatated proteins, either in the ELISA titers (p>0.05) or in the in vitro growth inhibiton assay (GIA) by sera, as well as total IgG (p>0.05).
Briefly, in this study, we created a panel of 17 mutant proteins of PfCP-2.9 with single amino acid substitution. With the mAbs against PfCP-2.9 prepared in previous work, we have mapped some epitopes of the vaccine candidate by Western Blot and ELISA, and raised the possible biological function of these epitopes. Recognition of the mutant proteins by sera from natural infections was also investigated, and the results showed that the binding of some mutant proteins was altered by the sera samples, compared with the binding of the wild-type protein. The data obtained may prove to be valuable and helpful for designing more effective malaria vaccines against blood-stage parasites in future studies.
引文
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2. Thomas AW, Deans JA, Mitchell GH, Alderson T, Cohen S:The Fab fragments of monoclonal IgG to a merozoite surface antigen inhibit Plasmodium knowlesi invasion of erythrocytes. Molecular and biochemical parasitology 1984, 13(2):187-199. 3. Egan AF, Burghaus P, Druilhe P, Holder AA, Riley EM:Human antibodies to the 19kDa C-terminal fragment of Plasmodium falciparum merozoite surface protein 1 inhibit parasite growth in vitro. Parasite'immunology 1999, 21(3):133-139.
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6. Dluzewski AR, Ling IT, Hopkins JM, Grainger M, Margos G, Mitchell GH, Holder AA, Bannister LH:Formation of the food vacuole in Plasmodium falciparum:a potential role for the 19 kDa fragment of merozoite surface protein 1 (MSP1(19)). PloS one 2008,3(8):e3085.
7. Gilson PR, O'Donnell RA, Nebl T, Sanders PR, Wickham ME, McElwain TF, de Koning-Ward TF, Crabb BS:MSP1(19) miniproteins can serve as targets for invasion inhibitory antibodies in Plasmodium falciparum provided they contain the correct domains for cell surface trafficking. Mol Microbiol 2008, 68(1):124-138.
8. Ahlborg N, Ling IT, Howard W, Holder AA, Riley EM:Protective immune responses to the 42-kilodalton (kDa) region of Plasmodium yoelii merozoite surface protein 1 are induced by the C-terminal 19-kDa region but not by the adjacent 33-kDa region. Infection and immunity 2002,70(2):820-825.
9. Cooper JA, Cooper LT, Saul AJ:Mapping of the region predominantly recognized by antibodies to the Plasmodium falciparum merozoite surface antigen MSA 1. Molecular and biochemical parasitology 1992,51(2):301-312.
10. Guevara Patino JA, Holder AA, McBride JS, Blackman MJ:Antibodies that inhibit malaria merozoite surface protein-1 processing and erythrocyte invasion are blocked by naturally acquired human antibodies. The Journal of experimental medicine 1997,186(10):1689-1699.
11. Morgan WD, Birdsall B, Frenkiel TA, Gradwell MG, Burghaus PA, Syed SE, Uthaipibull C, Holder AA, Feeney J:Solution structure of an EGF module pair from the Plasmodium falciparum merozoite surface protein 1. Journal of molecular biology 1999,289(1):113-122.
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