Primary human trophoblasts and the transfer of viral resistance

描述（由申请人提供）：本申请的总体目标是破译人胎盘滋养层用于抵抗病毒感染并局部和全身传递抗病毒信号的新机制。微生物从母体宿主到胎盘的血源性传播可能对发育中的胚胎产生破坏性后果。此外，即使没有垂直传播，危害产妇健康的病毒病原体也可能危及妊娠结果。胎盘滋养层与母体血液直接接触，构成主要的胎儿-胎盘屏障，并能够与母体局部和全身环境相互作用，包括母体免疫系统的组分和细胞屏障，如微血管内皮。拟议的研究代表了病毒学和胎盘生物学专业知识的协同相互作用，导致了一种跨学科的追求，将滋养层特异性microRNA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，原代人滋养层细胞对各种无关病毒的感染具有高度抗性，并且非滋养层细胞可以通过靶向表达原代滋养层细胞衍生的microRNA来赋予这种抗性。我们计划确定介导这种效应的特定microRNA，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减弱病毒复制的手段。我们将分析滋养层microRNA在自噬调控中的作用，并研究可能允许某些病毒逃避这条细胞防线的途径。因此，我们的拨款提案超越了对病毒诱导的损伤机制的研究，而是确定了令人兴奋的新分子途径，这些分子途径可能会转移对病毒感染的先天和适应性反应。总之，我们确定了一种新的途径，可传播的胎盘抵抗病毒病原体。在破译构成该途径的潜在机制时，我们不仅可以阐明滋养层抵抗病原体的基础，而且还可以为旨在减轻和/或预防病毒感染的创新疗法的开发提供信息，从而减少感染相关的胎儿-母体发病率和死亡率的负担。 公共卫生相关性：妊娠期间病毒病原体感染是孕产妇发病的一个重要来源，并可能对胚胎发育造成破坏性后果，包括流产。我们发现了一种特殊的胎盘防御机制，可以抑制胎盘和非胎盘细胞的病毒感染，这可能在制定减轻病原体介导的胎盘感染和胎儿-母体疾病的策略中发挥关键作用。

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. PUBLIC HEALTH RELEVANCE: Infections by viral pathogens during pregnancy are a significant source of maternal morbidity, and can have devastating developmental consequences to the embryo, including pregnancy loss. We have uncovered an extraordinary placental defense mechanism to suppress viral infections of placental and non-placental cells, which may play a pivotal role in developing strategies for mitigating pathogen-mediated placental infection and feto-maternal disease.