Rapid identification of genes controlling virulence and immunity in malaria parasites.
Rapid identification of genes controlling virulence and immunity in malaria parasites.
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DOI：
10.1371/journal.ppat.1006447
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发表时间：
2017-07
期刊：
影响因子：
6.7
通讯作者：
Culleton R
中科院分区：
文献类型：
--
作者：
Abkallo HM;Martinelli A;Inoue M;Ramaprasad A;Xangsayarath P;Gitaka J;Tang J;Yahata K;Zoungrana A;Mitaka H;Acharjee A;Datta PP;Hunt P;Carter R;Kaneko O;Mustonen V;Illingworth CJR;Pain A;Culleton R
确定影响疾病严重程度的表型的遗传决定因素对于设计新的疟疾干预措施至关重要。在这里，我们提出了一种快速的全基因组方法，能够通过单基因或等位基因分辨率的单一实验来识别疟疾寄生虫内医学上相关表型的多个遗传驱动因素。在一项原理证明研究中，我们发现红细胞结合样蛋白(EBL)结合区域中先前未描述的单核苷酸多态性导致突变的啮齿动物疟疾寄生虫约氏疟原虫的红细胞侵袭性发生戏剧性变化。在同一实验中，我们将裂殖子表面蛋白1(MSP1)和其他多态蛋白作为菌株特异性免疫的主要靶标。利用等位基因替换，我们提供了控制寄生虫血液期生长速度的EBL基因替换的功能验证。加深对疟疾遗传学的了解是对抗该疾病构成的威胁的关键一步。在这里，我们使用一种新的方法来研究寄生虫的两个重要属性：寄生虫在单个宿主内的生长速度，以及寄生虫受宿主免疫系统影响的方式。两种不同生物学特性的疟疾菌株在蚊子中杂交，产生一个杂交种群，然后在幼稚和接种疫苗的小鼠身上种植。带有促进生长或免疫逃避的基因的寄生虫在自然选择中受到青睐，这在交叉种群的遗传构成上留下了特征。我们描述了一种新的数学方法来解释这个信号，识别寄生虫种群中的选定基因。我们发现了新的遗传变异，在小鼠疟疾品系中表达了宿主内生长和对宿主免疫的抵抗力。实验验证突出了这一快速实验过程对疟疾生物学的洞察能力。
Identifying the genetic determinants of phenotypes that impact disease severity is of fundamental importance for the design of new interventions against malaria. Here we present a rapid genome-wide approach capable of identifying multiple genetic drivers of medically relevant phenotypes within malaria parasites via a single experiment at single gene or allele resolution. In a proof of principle study, we found that a previously undescribed single nucleotide polymorphism in the binding domain of the erythrocyte binding like protein (EBL) conferred a dramatic change in red blood cell invasion in mutant rodent malaria parasites Plasmodium yoelii. In the same experiment, we implicated merozoite surface protein 1 (MSP1) and other polymorphic proteins, as the major targets of strain-specific immunity. Using allelic replacement, we provide functional validation of the substitution in the EBL gene controlling the growth rate in the blood stages of the parasites. Developing a greater understanding of malaria genetics is a key step in combating the threat posed by the disease. Here we use a novel approach to study two important properties of the parasite; the rate at which parasites grow within a single host, and the means by which parasites are affected by the host immune system. Two malaria strains with different biological properties were crossed in mosquitoes to produce a hybrid population, which was then grown in naïve and vaccinated mice. Parasites with genes conveying increased growth or immune evasion are favoured under natural selection, leaving a signature on the genetic composition of the cross population. We describe a novel mathematical approach to interpret this signature, identifying selected genes within the parasite population. We discover new genetic variants conveying increased within-host growth and resistance to host immunity in a mouse malaria strain. Experimental validation highlights the ability of this rapid experimental process for generating insights into malaria biology.
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影响因子：
6.7
作者：
Blake DP;Billington KJ;Copestake SL;Oakes RD;Quail MA;Wan KL;Shirley MW;Smith AL
通讯作者：
Smith AL
影响因子：
6.7
作者：
Abkallo HM;Tangena JA;Tang J;Kobayashi N;Inoue M;Zoungrana A;Colegrave N;Culleton R
通讯作者：
Culleton R
影响因子：
10.7
作者：
Illingworth, Christopher J. R.;Parts, Leopold;Mustonen, Ville
通讯作者：
Mustonen, Ville
影响因子：
14.9
作者：
Ceroni, Alessio;Passerini, Andrea;Vullo, Alessandro;Frasconi, Paolo
通讯作者：
Frasconi, Paolo
影响因子：
5.8
作者：
Arnold, K;Bordoli, L;Schwede, T
通讯作者：
Schwede, T