Host kinase regulation of Plasmodium vivax dormant and replicating liver stages.
Host kinase regulation of Plasmodium vivax dormant and replicating liver stages.
复制标题
间日疟原虫休眠和复制肝脏阶段的宿主激酶调节。
DOI：
10.1101/2023.11.13.566868
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Kaushansky,Alexis
中科院分区：
文献类型：
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作者：
Glennon,ElizabethKk;Wei,Ling;Roobsoong,Wanlapa;Primavera,VeronicaI;Tongogara,Tinotenda;Yee,ConradB;Sattabongkot,Jetsumon;Kaushansky,Alexis
在传播到肝脏后，间日疟原虫形成复制的裂殖体，裂殖体继续发起血液阶段的感染，或者休眠的催眠体，在初始感染后数周至数月重新激活。现场间日疟原虫的表型差异很大，包括裂殖体和催眠体形成的比率以及复发的频率和时间。有证据表明，寄生虫的遗传和环境因素都是造成这种异质性的原因。我们以前证明了关于一组具有重叠靶点的激酶抑制剂对疟原虫肝期感染的影响的数据，结合称为激酶回归(KIR)的计算方法，可以用来揭示新的宿主感染调节因子。在这里，我们应用KIR来评估间日疟原虫肝期寄生虫对宿主激酶活性变化的易感程度。我们确定了宿主激酶的一个子集在调节裂殖体和催眠体感染和裂殖体大小中的作用，并表征了不同寄生虫形式和多个患者分离株之间宿主磷信号依赖的重叠和可变性。引人注目的是，我们的数据表明，间日疟原虫各分离株之间的寄主依赖性存在变异性，这表明田间观察到的间日疟原虫的异质性可能是一个来源。
Upon transmission to the liver, Plasmodium vivax parasites form replicating schizonts, which continue to initiate blood-stage infection, or dormant hypnozoites that reactivate weeks to months after initial infection. P. vivax phenotypes in the field vary significantly, including the ratio of schizonts to hypnozoites formed and the frequency and timing of relapse. Evidence suggests that both parasite genetics and environmental factors underly this heterogeneity. We previously demonstrated that data on the effect of a panel of kinase inhibitors with overlapping targets on Plasmodium liver stage infection, in combination with a computational approach called kinase regression (KiR), can be used to uncover novel host regulators of infection. Here, we applied KiR to evaluate the extent to which P. vivax liver-stage parasites are susceptible to changes in host kinase activity. We identified a role for a subset of host kinases in regulating schizont and hypnozoite infection and schizont size and characterized overlap as well as variability in host phosphosignaling dependencies between parasite forms and across multiple patient isolates. Striking, our data point to variability in host dependencies across P. vivax isolates, suggesting one possible origin of the heterogeneity observed across P. vivax in the field.