Antibody targeting of a specific region of Pfs47 blocks Plasmodium falciparum malaria transmission.
Antibody targeting of a specific region of Pfs47 blocks Plasmodium falciparum malaria transmission.
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DOI：
10.1038/s41541-018-0065-5
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发表时间：
2018
期刊：
影响因子：
9.2
通讯作者：
Barillas-Mury C
中科院分区：
文献类型：
--
作者：
Canepa GE;Molina-Cruz A;Yenkoidiok-Douti L;Calvo E;Williams AE;Burkhardt M;Peng F;Narum D;Boulanger MJ;Valenzuela JG;Barillas-Mury C
传播阻断疫苗的基础是在脊椎动物宿主中激发抗体反应，扰乱蚊媒中寄生虫的发展，防止疟疾传播。表面蛋白Pfs47存在于恶性疟原虫配子体和雌配子中。对Pfs47作为疫苗靶点的潜力进行了评估。可溶性全长重组蛋白由三个结构域组成，以硫氧还蛋白融合蛋白(T-Pfs47)的形式在大肠杆菌中表达。该蛋白具有免疫原性，可获得多克隆和单抗，但不具有传播阻断活性(TBA)。在T-Pfs47免疫后，所有14株单抗均针对结构域1或3，但不针对结构域2(D2)，多克隆小鼠免疫后对D2的免疫反应性也很低。通过用半胱氨酸取代丙氨酸(C230A和C260A)，破坏D2中预测的二硫键，允许在大肠杆菌中表达重组D2蛋白。针对D2的单抗和该结构域的缺失蛋白的组合，使我们能够定位中央52个氨基酸(AA)区域，其中抗体结合提供强大的TBA(78-99%)。这种52氨基酸抗原具有免疫原性和保守性，全世界只有7种单倍型具有96-98%的同源性。观察到的TBA既不需要人类补体，也不需要类似蚊子补体的系统。观察到卵母细胞数量和卵母细胞特异性转录本的显著减少，表明抗体正在与雌配子细胞相互作用，阻止受精。疟疾疫苗的传播阻断活性(TBA)可能针对人类宿主或蚊子媒介内的寄生虫阶段。由美国国立卫生研究院的Carolina Barillas-Mury领导的一个团队设计了一种针对Pfs47蛋白的疫苗，Pfs47主要存在于恶性疟原虫配子细胞表面。全长的Pfs47不会引起总胆汁酸；然而，基于Pfs47‘S结构域2中心区的修饰版本的抗原在小鼠中产生具有有效总胆汁酸的抗体。这种TBA不依赖于人类补体或类似蚊子补体的系统。相反，这种TBA抗体可能通过干扰雌配子体和阻止受精来发挥作用。Pfs47区在恶性疟原虫中高度保守，提示存在广泛有效的疫苗或与其他疫苗靶抗原协同作用的可能性。
Transmission-blocking vaccines are based on eliciting antibody responses in the vertebrate host that disrupt parasite development in the mosquito vector and prevent malaria transmission. The surface protein Pfs47 is present in Plasmodium falciparum gametocytes and female gametes. The potential of Pfs47 as a vaccine target was evaluated. Soluble full-length recombinant protein, consisting of three domains, was expressed in E. coli as a thioredoxin fusion (T-Pfs47). The protein was immunogenic, and polyclonal and monoclonal antibodies (mAb) were obtained, but they did not confer transmission blocking activity (TBA). All fourteen mAb targeted either domains 1 or 3, but not domain 2 (D2), and immune reactivity to D2 was also very low in polyclonal mouse IgG after T-Pfs47 immunization. Disruption of the predicted disulfide bond in D2, by replacing cysteines for alanines (C230A and C260A), allowed expression of recombinant D2 protein in E. coli. A combination of mAbs targeting D2, and deletion proteins from this domain, allowed us to map a central 52 amino acid (aa) region where antibody binding confers strong TBA (78-99%). This 52 aa antigen is immunogenic and well conserved, with only seven haplotypes world-wide that share 96–98% identity. Neither human complement nor the mosquito complement-like system are required for the observed TBA. A dramatic reduction in ookinete numbers and ookinete-specific transcripts was observed, suggesting that the antibodies are interacting with female gametocytes and preventing fertilization. Transmission blocking activity (TBA) of malaria vaccines can potentially target parasite stages either within the human host or the mosquito vector. A team led by Carolina Barillas-Mury at the National Institutes of Health, USA, engineered a vaccine targeting the protein Pfs47 which is present mainly on the surface of Plasmodium falciparum gametocytes. Full-length Pfs47 elicits no TBA; however, an antigen based on a modified version of the central region of Pfs47’s domain 2 generates antibodies with potent TBA in mice. This TBA is independent of human complement or a mosquito complement-like system. Instead, such TBA antibodies likely function by interfering with female gametocytes and preventing fertilization. The Pfs47 region eliciting potent TBA is highly conserved in P. falciparum, suggesting the possibility of a broadly-effective vaccine or synergy with other vaccine target antigens.
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影响因子：
3.1
作者：
Ukegbu CV;Akinosoglou KA;Christophides GK;Vlachou D
通讯作者：
Vlachou D
DOI：
10.4103/0971-5916.191927
发表时间：
2016-06
期刊：
The Indian journal of medical research
影响因子：
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作者：
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影响因子：
6.7
作者：
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通讯作者：
Sinden RE
DOI：
10.1126/science.1235264
发表时间：
2013-05-24
期刊：
Science (New York, N.Y.)
影响因子：
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作者：
Molina-Cruz A;Garver LS;Alabaster A;Bangiolo L;Haile A;Winikor J;Ortega C;van Schaijk BC;Sauerwein RW;Taylor-Salmon E;Barillas-Mury C
通讯作者：
Barillas-Mury C
DOI：
10.1074/mcp.ra117.000036
发表时间：
2020-01
期刊：
Molecular & cellular proteomics : MCP
影响因子：
--
作者：
Nikolaeva D;Illingworth JJ;Miura K;Alanine DGW;Brian IJ;Li Y;Fyfe AJ;Da DF;Cohuet A;Long CA;Draper SJ;Biswas S
通讯作者：
Biswas S