Dissection of the in vitro developmental program of Hammondia hammondi reveals a link between stress sensitivity and life cycle flexibility in Toxoplasma gondii.
Dissection of the in vitro developmental program of Hammondia hammondi reveals a link between stress sensitivity and life cycle flexibility in Toxoplasma gondii.
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DOI：
10.7554/elife.36491
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发表时间：
2018-05-22
期刊：
影响因子：
7.7
通讯作者：
Boyle JP
中科院分区：
文献类型：
--
作者：
Sokol SL;Primack AS;Nair SC;Wong ZS;Tembo M;Verma SK;Cerqueira-Cezar CK;Dubey JP;Boyle JP
大多数真核寄生虫是专性的异种寄生虫，需要不同宿主物种的顺序感染才能生存。弓形虫是这一规则的罕见例外，具有独特的兼性杂氧生活史。为了了解这一现象的起源，我们比较了弓形虫及其专性异株近亲Hammondia hammondi的发育和应激反应，并鉴定了与弓形虫不同的多种生长状态。其中，最显著的区别是，哈蒙迪对强烈诱导弓形虫形成包囊的应激源是不敏感的，这一点最显著地反映在其在应激暴露后不变的转录组中。我们还发现，哈蒙迪可以在体外繁殖长达8天后，我们利用这一点，我们获得了第一个转基因哈蒙迪株。总体而言，我们的数据显示，哈蒙迪疟原虫的生长受到严格的调控，是有别于弓形虫速殖子的独特的生活期，这意味着应激敏感性是一种潜在的发育创新，增加了弓形虫生活史的灵活性。全世界有超过10亿人被一种名为弓形虫的寄生虫感染，通常是终身感染。大多数情况下，寄生虫处于休眠状态，不会引起任何症状。然而，寄生虫可以重新激活，这对免疫系统较弱的人来说可能是致命的。目前还没有药物可以杀死处于休眠阶段的弓形虫。弓形虫如此普遍的可能原因之一是它很容易从一个宿主传播到另一个宿主，并且抵抗检测和治疗。像许多寄生虫一样，弓形虫在其生命周期中会感染多个宿主：它在其最终宿主猫身上有性繁殖，在其中间宿主(几乎包括所有温血动物)中无性繁殖。与大多数寄生虫不同，所有宿主都可以将弓形虫传播给其他宿主，使其成为一种非常灵活的寄生虫。然而，其活着的近亲Hammondia hammondi只能从确定的宿主传播到中间宿主，反之亦然。这种差异的原因尚不清楚，但这些物种之间的比较有望有助于揭示弓形虫是如何成为如此混杂的寄生虫的。现在，索科尔，普里马克等人。报告说，汉蒙迪弓形虫和弓形虫之间的显著区别是适应环境变化的能力。虽然哈蒙迪弓形虫的生长方式非常严格和僵硬，但弓形虫可以感知环境，并相应地改变其生长速度。这一点很重要，因为它将允许弓形虫生长，直到宿主免疫反应被激活，然后弓形虫就可以迅速休眠，躲避这些宿主防御。Sokol，Primack等人。提出这种独特的适应可能帮助弓形虫成为今天这样在全球范围内成功的寄生虫，并解释为什么哈蒙迪弓形虫的致命性要低得多。弓形虫也有可能在休眠一段时间后重新激活，因为它能感觉到环境的变化。如果是这样的话，如果科学家能够识别出这一过程所需的传感器，也有可能针对它们并有效地阻止受感染人类的重新激活。比较弓形虫和哈蒙迪弓形虫可能会为识别这些传感器提供一个很好的方法。
Most eukaryotic parasites are obligately heteroxenous, requiring sequential infection of different host species in order to survive. Toxoplasma gondii is a rare exception to this rule, having a uniquely facultative heteroxenous life cycle. To understand the origins of this phenomenon, we compared development and stress responses in T. gondii to those of its its obligately heteroxenous relative, Hammondia hammondi and have identified multiple H. hammondi growth states that are distinct from those in T. gondii. Of these, the most dramatic difference was that H. hammondi was refractory to stressors that robustly induce cyst formation in T. gondii, and this was reflected most dramatically in its unchanging transcriptome after stress exposure. We also found that H. hammondi could be propagated in vitro for up to 8 days post-excystation, and we exploited this to generate the first ever transgenic H. hammondi line. Overall our data show that H. hammondi zoites grow as stringently regulated, unique life stages that are distinct from T. gondii tachyzoites, and implicate stress sensitivity as a potential developmental innovation that increased the flexibility of the T. gondii life cycle. Over a billion people worldwide are infected, often for life, by a parasite known as Toxoplasma gondii. Most of the time, the parasites remain in a dormant state and cause no symptoms. However, the parasites can reactivate, which can be fatal for people with weaker immune systems. Currently no drugs can kill the dormant stages of T. gondii. One of the possible reasons T. gondii is so widespread is because it easily passes from host to host, and resists both detection and treatment. Like many parasites, T. gondii infects multiple hosts during its life cycle: it reproduces sexually in its ‘definitive' host, the cat, and reproduces asexually in its ‘intermediate’ hosts, which include virtually all warm-blooded animals. Unlike most parasites, all hosts can transmit T. gondii to other hosts, making it a very flexible parasite. However, its closest living relative, Hammondia hammondi, can only be transmitted from a definitive host to an intermediate host, or vice versa. The reason for this difference remains unclear, but comparisons between these species can hopefully help uncover how T. gondii came to be such a promiscuous parasite. Now, Sokol, Primack et al. report that a dramatic difference between H. hammondi and T. gondii is the ability to adapt to changes in the environment. While H. hammondi grows in a very strict and inflexible way, T. gondii can sense its environment and change its growth rate accordingly. This is important because it would allow T. gondii to grow until the host immune response is activated, at which time T. gondii can then quickly become dormant and hide from these host defences. Sokol, Primack et al. suggest that this unique adaptation may have helped T. gondii to become the globally successful parasite that it is today, and explain why H. hammondi is much less lethal. It is also possible that T. gondii reactivates after periods of dormancy because it senses changes in its environment. If so, and if scientists can identify the sensors required for this, it may also be possible to target them and effectively block reactivation in infected humans. Comparing T. gondii with H. hammondi may provide a good way to identify these sensors.