Structure-guided insights into potential function of novel genetic variants in the malaria vaccine candidate PfRh5.
Structure-guided insights into potential function of novel genetic variants in the malaria vaccine candidate PfRh5.
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DOI：
10.1038/s41598-022-23929-9
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发表时间：
2022-11-12
影响因子：
4.6
通讯作者：
Bei, Amy K.
中科院分区：
文献类型：
--
作者：
Mangou, Khadidiatou;Moore, Adam J.;Thiam, Laty Gaye;Ba, Aboubacar;Orfano, Alessandra;Desamours, Ife;Ndegwa, Duncan Ndungu;Goodwin, Justin;Guo, Yicheng;Sheng, Zizhang;Patel, Saurabh D.;Diallo, Fatoumata;Sene, Seynabou D.;Pouye, Mariama N.;Faye, Awa Thioub;Thiam, Alassane;Nunez, Vanessa;Diagne, Cheikh Tidiane;Sadio, Bacary Djilocalisse;Shapiro, Lawrence;Faye, Ousmane;Mbengue, Alassane;Bei, Amy K.
最近全球减少疟疾死亡人数的工作停滞不前，这使得研制一种非常有效的疫苗至关重要。开发有效疫苗的一个主要挑战是恶性疟原虫抗原的广泛多样性。虽然遗传多样性在免疫逃避中起着重要作用，并且是发展天然和疫苗诱导的保护性免疫的障碍，但在评估疟疾候选疫苗时，它一直没有得到优先考虑。本研究使用基因组方法评估下一代疟疾候选疫苗PfRh5的遗传多样性。我们利用靶向深度扩增子测序技术，鉴定了来自塞内加尔南部189份恶性疟原虫阳性样本中PfRh5（网状细胞结合蛋白同源物5）的非同义单核苷酸多态性（SNPs），并鉴定出74个新的snp。我们评估了这些SNP的人群患病率以及个体样本中的频率，发现每个位点只有一个SNP C203Y存在。许多snp是个体所特有的，超过90%的snp仅在一个感染个体中被发现。除了人群患病率外，我们还评估了个体水平的SNP频率，结果显示一些SNP是显性的（在多基因组样本中频率大于25%），而大多数SNP是罕见的，在给定位置的参考文献中，只有2%或更少的总读取量。结构建模发现3个新的snp发生在抑制单克隆抗体结合的表位下，可能影响免疫逃避，而其他snp预计会影响PfRh5的结构或与受体或结合伙伴的相互作用。我们的数据表明，PfRh5表现出比之前描述的更大的遗传多样性，但需要注意的是，大多数发现的snp在个体中总体频率较低，在人群中普遍存在。结构研究表明，新的snp可能对PfRh5受体结合、复合物形成或免疫逃避具有功能意义，支持PfRh5作为有效疟疾疫苗靶点的持续验证和PfRh5疫苗的开发。
The recent stall in the global reduction of malaria deaths has made the development of a highly effective vaccine essential. A major challenge to developing an efficacious vaccine is the extensive diversity of Plasmodium falciparum antigens. While genetic diversity plays a major role in immune evasion and is a barrier to the development of both natural and vaccine-induced protective immunity, it has been under-prioritized in the evaluation of malaria vaccine candidates. This study uses genomic approaches to evaluate genetic diversity in next generation malaria vaccine candidate PfRh5. We used targeted deep amplicon sequencing to identify non-synonymous Single Nucleotide Polymorphisms (SNPs) in PfRh5 (Reticulocyte-Binding Protein Homologue 5) in 189 P. falciparum positive samples from Southern Senegal and identified 74 novel SNPs. We evaluated the population prevalence of these SNPs as well as the frequency in individual samples and found that only a single SNP, C203Y, was present at every site. Many SNPs were unique to the individual sampled, with over 90% of SNPs being found in just one infected individual. In addition to population prevalence, we assessed individual level SNP frequencies which revealed that some SNPs were dominant (frequency of greater than 25% in a polygenomic sample) whereas most were rare, present at 2% or less of total reads mapped to the reference at the given position. Structural modeling uncovered 3 novel SNPs occurring under epitopes bound by inhibitory monoclonal antibodies, potentially impacting immune evasion, while other SNPs were predicted to impact PfRh5 structure or interactions with the receptor or binding partners. Our data demonstrate that PfRh5 exhibits greater genetic diversity than previously described, with the caveat that most of the uncovered SNPs are at a low overall frequency in the individual and prevalence in the population. The structural studies reveal that novel SNPs could have functional implications on PfRh5 receptor binding, complex formation, or immune evasion, supporting continued efforts to validate PfRh5 as an effective malaria vaccine target and development of a PfRh5 vaccine.
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DOI：
10.1056/nejmoa1008115
发表时间：
2011-09-15
期刊：
The New England journal of medicine
影响因子：
--
作者：
Thera MA;Doumbo OK;Coulibaly D;Laurens MB;Ouattara A;Kone AK;Guindo AB;Traore K;Traore I;Kouriba B;Diallo DA;Diarra I;Daou M;Dolo A;Tolo Y;Sissoko MS;Niangaly A;Sissoko M;Takala-Harrison S;Lyke KE;Wu Y;Blackwelder WC;Godeaux O;Vekemans J;Dubois MC;Ballou WR;Cohen J;Thompson D;Dube T;Soisson L;Diggs CL;House B;Lanar DE;Dutta S;Heppner DG Jr;Plowe CV
通讯作者：
Plowe CV
影响因子：
17.1
作者：
Takala SL;Coulibaly D;Thera MA;Batchelor AH;Cummings MP;Escalante AA;Ouattara A;Traoré K;Niangaly A;Djimdé AA;Doumbo OK;Plowe CV
通讯作者：
Plowe CV
影响因子：
3
作者：
Ajibaye, Olusola;Osuntoki, Akinniyi A.;Amambua-Ngwa, Alfred
通讯作者：
Amambua-Ngwa, Alfred
DOI：
10.1056/nejmoa1515257
发表时间：
2016-06-30
期刊：
The New England journal of medicine
影响因子：
--
作者：
Olotu A;Fegan G;Wambua J;Nyangweso G;Leach A;Lievens M;Kaslow DC;Njuguna P;Marsh K;Bejon P
通讯作者：
Bejon P
影响因子：
64.8
作者：
Crosnier, Cecile;Bustamante, Leyla Y.;Bartholdson, S. Josefin;Bei, Amy K.;Theron, Michel;Uchikawa, Makoto;Mboup, Souleymane;Ndir, Omar;Kwiatkowski, Dominic P.;Duraisingh, Manoj T.;Rayner, Julian C.;Wright, Gavin J.
通讯作者：
Wright, Gavin J.