Primary human trophoblasts and the transfer of viral resistance

描述(申请人提供)：本申请的首要目标是破译人类胎盘滋养层细胞用来抵抗病毒感染的新机制，并局部和系统地传递抗病毒信号。微生物从母体到胎盘的血源性传播可能会对发育中的胚胎造成毁灭性的后果。此外，即使在没有垂直传播的情况下，危害产妇健康的病毒病原体也可能危及妊娠结局。胎盘滋养层细胞位于与母体血液直接接触的位置，构成了主要的胎盘屏障，并能够与母体局部和全身环境接触，包括母体免疫系统的组成部分和细胞屏障，如微血管内皮细胞。这项拟议的研究代表了病毒学和胎盘生物学专业知识的协同作用，导致了一项跨学科的追求，将滋养细胞特异性microRNAs的功能与抑制病毒复制的独特细胞途径相结合。我们的初步数据表明，原代人类滋养层细胞对多种无关病毒的感染具有高度抵抗力，非滋养层细胞可以通过靶向表达原始滋养层细胞来源的microRNAs来获得这种抵抗力。我们计划确定介导这一效应的特定microRNAs，并确定microRNA转运到非滋养层靶细胞的机制，在那里它们刺激自噬，作为抑制病毒复制的一种手段。我们将分析滋养层微RNA在自噬调节中的作用，并检查可能允许某些病毒逃避这条细胞防线的途径。因此，我们的拨款建议超越了对病毒诱导的损伤机制的研究，而是确定了可能转移对病毒感染的先天和适应性反应的令人兴奋的新的分子途径。我们共同确定了胎盘对病毒病原体的可传播性耐药的新途径。在破译构成这一途径的潜在机制时，我们不仅可以阐明滋养层抵抗病原体的基础，还可以为开发旨在减轻和/或预防病毒感染的创新疗法提供信息，从而减少感染相关母婴发病率和死亡率的负担。

DESCRIPTION (provided by applicant): The overarching goal of this application is to decipher novel mechanisms utilized by human placental trophoblasts to resist viral infections and to communicate antiviral signals locally and systemically. Hematogenous spread of microbes from the maternal host to the placenta can have devastating consequences to the developing embryo. Moreover, even in the absence of vertical transmission, viral pathogens that compromise maternal health may jeopardize pregnancy outcome. Located in direct contact with maternal blood, the placental trophoblasts constitute the cardinal feto-placental barrier, and are capable of interfacing with the maternal local and systemic environments, including components of the maternal immune system and cellular barriers such as the microvascular endothelium. The proposed research represents the synergistic interaction of expertise in virology and placental biology, resulting in a transdisciplinary pursuit that integrates the function of trophoblast-specific microRNAs with distinctive cellular pathways that suppress viral replication. Our preliminary data indicate that primary human trophoblasts are highly resistant to infection by a wide range of unrelated viruses, and that non-trophoblastic cells can be endowed with this resistance by targeted expression of primary trophoblasts-derived microRNAs. We plan to identify the specific microRNAs that mediate this effect, and define mechanisms of microRNA transport to non-trophoblastic target cells, where they stimulate autophagy as a means to attenuate viral replication. We will analyze the role of trophoblastic microRNAs in the regulation of autophagy, and examine the pathways that may allow certain viruses to evade this line of cellular defense. Thus, our grant proposal goes beyond investigation of the mechanisms of virus-induced injury, and instead identifies exciting new molecular pathways that may transfer innate and adaptive responses to virus infection. Together, we identified a novel pathway for transmissible placental resistance to viral pathogens. In deciphering the underlying mechanisms that constitute this pathway we may not only illuminate the basis of trophoblast resistance to pathogens, but also inform the development of innovative therapeutics designed to mitigate and/or prevent viral infections, thus reducing the burden of infection related feto-maternal morbidity and mortality.