The human malaria parasite Plasmodium falciparum can sense environmental changes and respond by antigenic switching.
The human malaria parasite Plasmodium falciparum can sense environmental changes and respond by antigenic switching.
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DOI：
10.1073/pnas.2302152120
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发表时间：
2023-04-25
影响因子：
11.1
通讯作者：
Deitsch, Kirk W.
中科院分区：
文献类型：
--
作者：
Schneider, Victoria M.;Visone, Joseph E.;Harris, Chantal T.;Florini, Francesca;Hadjimichael, Evi;Zhang, Xu;Gross, Mackensie R.;Rhee, Kyu Y.;Mamoun, Choukri Ben;Kafsack, Bjorn F. C.;Deitsch, Kirk W.
引起疟疾的寄生虫通过系统地改变它们暴露在受感染细胞表面的抗原来避免人类免疫反应的破坏。这个过程称为抗原变异，是造成该疾病的慢性性质和毒力的原因。寄生虫进行抗原转换的机制仍不清楚；然而，人们假设这一过程在感染过程中随机发生。在这里，我们证明寄生虫可以感知环境的变化，并根据这些变化进行抗原转换。这意味着宿主和寄生虫之间的相互作用比以前理解的要复杂得多，并且表明寄生虫已经进化到在需要时进行抗原转换，例如响应免疫识别。人类疟疾寄生虫恶性疟原虫的主要抗原和毒力决定因子是一种称为 PfEMP1 的表面蛋白变体。不同形式的 PfEMP1 由名为 var 的多拷贝基因家族编码，活跃基因之间的切换使寄生虫能够逃避人类宿主的抗体反应。 var 基因转换是维持慢性感染的关键；然而，控制开关的因素尚不清楚，尽管有人认为开关以恒定频率发生，几乎没有或没有环境影响。 var 基因转录通过组蛋白甲基转移酶 (HMT) 的活性进行表观遗传控制。模型系统的研究表明，代谢和基因表达的表观遗传控制通过细胞内 S-腺苷甲硫氨酸 (SAM) 的可用性联系在一起，SAM 是生物甲基化修饰中的主要甲基供体，它可以根据营养的可用性而波动。为了确定环境条件和代谢变化是否会影响 var 基因表达，在改变了参与 SAM 代谢的营养物质浓度的培养基中培养恶性疟原虫。我们发现影响脂质代谢的条件会诱导 var 基因转换，这表明寄生虫可以通过改变 var 基因表达模式来响应环境变化。直接改变控制 SAM 水平的酶表达的基因修饰同样导致 var 基因表达的深刻变化，证实 SAM 可用性的变化调节 var 基因转换。这些观察结果直接挑战了恶性疟原虫抗原变异遵循内在的、程序化的转换率的范式，该转换率独立于任何外部刺激而运作。
The parasites that cause malaria avoid destruction by the human immune response by systematically changing the antigens they expose on the infected cell surface. This process, called antigenic variation, is responsible for the chronic nature and virulence of the disease. The mechanisms enabling parasites to undergo antigen switching remain unknown; however, it has been assumed that this process occurs stochastically over the course of an infection. Here we show that parasites can sense changes in their environment and undergo antigen switching in response to those changes. This implies a much more sophisticated interaction between host and parasite than was previously appreciated and suggests that parasites have evolved to undergo antigenic switching when needed, for example in response to immune recognition. The primary antigenic and virulence determinant of the human malaria parasite Plasmodium falciparum is a variant surface protein called PfEMP1. Different forms of PfEMP1 are encoded by a multicopy gene family called var, and switching between active genes enables the parasites to evade the antibody response of their human hosts. var gene switching is key for the maintenance of chronic infections; however, what controls switching is unknown, although it has been suggested to occur at a constant frequency with little or no environmental influence. var gene transcription is controlled epigenetically through the activity of histone methyltransferases (HMTs). Studies in model systems have shown that metabolism and epigenetic control of gene expression are linked through the availability of intracellular S-adenosylmethionine (SAM), the principal methyl donor in biological methylation modifications, which can fluctuate based on nutrient availability. To determine whether environmental conditions and changes in metabolism can influence var gene expression, P. falciparum was cultured in media with altered concentrations of nutrients involved in SAM metabolism. We found that conditions that influence lipid metabolism induce var gene switching, indicating that parasites can respond to changes in their environment by altering var gene expression patterns. Genetic modifications that directly modified expression of the enzymes that control SAM levels similarly led to profound changes in var gene expression, confirming that changes in SAM availability modulate var gene switching. These observations directly challenge the paradigm that antigenic variation in P. falciparum follows an intrinsic, programed switching rate, which operates independently of any external stimuli.
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影响因子：
3.7
作者：
Tuikue Ndam N;Bischoff E;Proux C;Lavstsen T;Salanti A;Guitard J;Nielsen MA;Coppée JY;Gaye A;Theander T;David PH;Deloron P
通讯作者：
Deloron P
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14.9
作者：
Deitsch, KW;Driskill, CL;Wellems, TE
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Wellems, TE
影响因子：
64.5
作者：
BARUCH, DI;PASLOSKE, BL;HOWARD, RJ
通讯作者：
HOWARD, RJ
影响因子：
4.6
作者：
Beri, Divya;Balan, Balu;Tatu, Utpal
通讯作者：
Tatu, Utpal
影响因子：
10.6
作者：
Gao X;Reid MA;Kong M;Locasale JW
通讯作者：
Locasale JW