Schistosoma mansoni alter transcription of immunomodulatory gene products following in vivo praziquantel exposure.
Schistosoma mansoni alter transcription of immunomodulatory gene products following in vivo praziquantel exposure.
复制标题
曼氏血吸虫体内暴露于吡喹酮后免疫调节基因产物转录的改变。
DOI：
10.1371/journal.pntd.0009200
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发表时间：
2021-03
影响因子：
3.8
通讯作者：
Chan JD
中科院分区：
文献类型：
--
作者：
McCusker P;Rohr CM;Chan JD
被忽视的热带疾病血吸虫病的控制几乎完全依赖于吡喹酮（PZQ）单一疗法。PZQ如何清除寄生虫感染仍然知之甚少。许多研究已经检查了PZQ对体外培养的蠕虫的影响，观察肌肉收缩等结果。然而，考虑到PZQ的半衰期短以及宿主免疫系统参与对动物模型中药物功效的重要性，蠕虫在体内暴露的条件可能与体外实验有很大不同。在这里，我们研究了体内暴露PZQ曼氏血吸虫的影响。促凋亡半胱天冬酶激活的测量显示，蠕虫死亡仅发生在寄生虫从肠系膜血管转移到肝脏后，在药物治疗后24小时达到峰值。这表明PZQ不是直接杀虫的，因为PZQ的半衰期在人类中约为2小时，在小鼠中约为30分钟，并且将注意力集中在蠕虫转移到肝脏后寄生虫与宿主免疫系统的相互作用上。从亚致死PZQ治疗后的小鼠肝脏收获的蠕虫的RNA-Seq揭示了推定的免疫调节和抗凝血基因产物的表达中的药物诱发的变化。这些基因产物中有几种定位于溶酶体食管，并可能分泌到宿主循环中。这些包括几种Kunitz型蛋白酶抑制剂，它们也存在于其他吸血动物的分泌物中。这些转录变化可能反映了寄生虫免疫逃避机制，在化疗反应，补体介导的攻击和宿主先天/体液免疫反应在寄生虫消除的作用。这些异构体之一，SmKI-1，已被证明具有免疫调节和抗凝血特性。这些数据提供了深入了解体内PZQ暴露对S. mansoni，以及寄生虫对化疗应激的转录反应。血吸虫病是由生活在循环系统中的寄生蠕虫引起的。虽然这种疾病在全世界感染了2亿多人，但治疗几乎完全依赖于一种药物吡喹酮，其机制知之甚少。在这项研究中，我们分析了吡喹酮治疗对吡喹酮化疗小鼠体内寄生虫基因表达的影响。尽管药物在体外对蠕虫的作用迅速，但我们发现体内的关键结果（细胞死亡和基因表达变化的测量）发生相对较晚（给药后12小时以上）。我们发现，蠕虫增加了免疫调节基因产物的表达，以响应吡喹酮，包括Kunitz型蛋白酶抑制剂，定位于蠕虫食道，并可能分泌到外部宿主环境。这是一类有趣的蛋白质，因为它们显示出抗凝血和免疫调节特性。这些基因产物的上调可能反映了寄生虫对化疗的免疫逃避机制。本研究通过观察吡喹酮在宿主免疫系统中对蠕虫的影响，深入了解吡喹酮的作用机制。
Control of the neglected tropical disease schistosomiasis relies almost entirely on praziquantel (PZQ) monotherapy. How PZQ clears parasite infections remains poorly understood. Many studies have examined the effects of PZQ on worms cultured in vitro, observing outcomes such as muscle contraction. However, conditions worms are exposed to in vivo may vary considerably from in vitro experiments given the short half-life of PZQ and the importance of host immune system engagement for drug efficacy in animal models. Here, we investigated the effects of in vivo PZQ exposure on Schistosoma mansoni. Measurement of pro-apoptotic caspase activation revealed that worm death occurs only after parasites shift from the mesenteric vasculature to the liver, peaking 24 hours after drug treatment. This indicates that PZQ is not directly schistocidal, since PZQ’s half-life is ~2 hours in humans and ~30 minutes in mice, and focuses attention on parasite interactions with the host immune system following the shift of worms to the liver. RNA-Seq of worms harvested from mouse livers following sub-lethal PZQ treatment revealed drug-evoked changes in the expression of putative immunomodulatory and anticoagulant gene products. Several of these gene products localized to the schistosome esophagus and may be secreted into the host circulation. These include several Kunitz-type protease inhibitors, which are also found in the secretomes of other blood feeding animals. These transcriptional changes may reflect mechanisms of parasite immune-evasion in response to chemotherapy, given the role of complement-mediated attack and the host innate/humoral immune response in parasite elimination. One of these isoforms, SmKI-1, has been shown to exhibit immunomodulatory and anti-coagulant properties. These data provide insight into the effect of in vivo PZQ exposure on S. mansoni, and the transcriptional response of parasites to the stress of chemotherapy. The disease schistosomiasis is caused by parasitic worms that live within the circulatory system. While this disease infects over 200 million people worldwide, treatment relies almost entirely on one drug, praziquantel, whose mechanism is poorly understood. In this study, we analyzed the effects of praziquantel treatment on the gene expression of parasites harvested from mice treated with praziquantel chemotherapy. Despite the rapid action of the drug on worms in vitro, we found that key outcomes in vivo (measurement of cell death and changes in gene expression) occurred relatively late (12+ hours after drug administration). We found that worms increased the expression of immunomodulatory gene products in response to praziquantel, including a Kunitz-type protease inhibitor that localized to the worm esophagus and may be secreted to the external host environment. These are an intriguing class of proteins, because they display anti-coagulant and immunomodulatory properties. Up-regulation of these gene products may reflect a parasite mechanism of immune-evasion in response to chemotherapy. This research provides insight into the mechanism of praziquantel by observing the effect of this drug on worms within the context of the host immune system.
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