CAREER: Rational design of a biomimetic nanomaterial library to probe mechanisms behind virus-induced immunopathology

PI: Scott, Evan a .提案号：1453576病毒是复杂的纳米级结构，它们进化出多种影响免疫系统的策略，以逃避检测并延长在宿主体内的生存时间。由此产生的病毒相关病理生理学伴随着旨在纠正被破坏的体内平衡的炎症免疫反应。病毒的形态、表面化学和细胞靶标引导了这种炎症，在许多情况下，这种炎症变得失调，导致一系列比原始病毒感染本身更有害的病理。因此，了解可以诱导特定免疫反应的特定炎症触发因素对于识别和治疗病毒诱导的病理以及影响广泛的炎症驱动疾病状态（包括动脉粥样硬化甚至季节性过敏）至关重要。不幸的是，造成这种有害免疫失调的具体机制往往过于复杂，难以分离。生物医学工程（BME）和纳米技术的最新进展现在允许对合成纳米结构的物理和化学特性进行前所未有的控制，这些纳米结构可以被设计成模拟纳米级病原体（如病毒）利用的感染机制。因此，本提案的研究目标是设计模拟病毒的纳米结构，作为研究病毒如何产生失调免疫反应的特定假设的工具。随着免疫学问题的工程方法变得越来越普遍，必须鼓励对免疫学和病毒学高度专业化领域感兴趣的未来学生和研究人员在BME领域从事职业。因此，该提案的教育目标是实施一个多管齐下的高中BME项目，让学生和他们的父母接触到BME职业所提供的各种机会。该提案旨在通过直接展示基于工程的技术和原理的好处，将BME扩展到生物科学的新专业领域。病毒免疫病理学研究的一个关键需求是一种可定制的原位方法，以探测特定的病毒结构、表面化学和生物分布如何导致病毒诱导的免疫系统失调。PI将合理设计病毒模拟聚合物纳米载体（NCs）文库，研究引发模型免疫调节失调性噬血细胞淋巴组织细胞病（HLH）的基本生化和细胞机制。在感染淋巴细胞脉络丛脑膜炎病毒（LCMV）后，可在几种小鼠模型中可控地诱导HLH。由于这些聚合物是惰性的，不会引起炎症反应，因此NCs可以被认为是“空白石板”，其中将加入各种各样的分子和免疫刺激剂，以控制运输到特定免疫细胞并激活它们。诱导HLH的基本炎症机制尚不清楚，因此该系统将通过将LCMV内的各种炎症成分（如糖蛋白包膜或RNA）划分为模拟病毒的生物分布和细胞内降解机制的单独nc来简化。NCs由嵌段共聚物组装而成，可以被设计成囊状和丝状纳米结构，分别针对多种和受限的炎症免疫细胞亚群。囊泡将通过诱导受控的全身细胞因子表达和效应T细胞活化来探索HLH的假设生化机制。这些细丝将研究浆细胞样树突状细胞的特定细胞作用，浆细胞样树突状细胞是一种炎症免疫细胞群，对对抗LCMV的免疫反应至关重要。通过使用受控的合成诱导感染，将确定导致HLH的关键lcmv相关炎症机制或其组合。这项工作将展示合理设计纳米材料的使用，以增强对特定炎症触发因素如何促进免疫病理学的理解。此外，在这些研究中收集的数据将为激发特异性和受控免疫反应所需的基本设计标准提供见解。

PI: Scott, Evan A.Proposal Number: 1453576Viruses are intricate nanoscale structures that have evolved diverse strategies of influencing the immune system to evade detection and prolong residence within their hosts. The resulting virus-related pathophysiology is accompanied by well-intended inflammatory immune responses aimed at rectifying a disrupted homeostasis. The morphology, surface chemistry, and cellular targets of viruses directs this inflammation, which in many instances becomes dysregulated, resulting in a range of pathologies that can be more harmful than the original viral infection itself. Understanding the specific inflammatory triggers that can induce a particular immunological response is therefore essential to the identification and treatment of virus-induced pathologies as well as impact a broad range of inflammation-driven disease states including atherosclerosis and even seasonal allergies. Unfortunately, the specific mechanisms that are responsible for such harmful immune dysregulations are often prohibitively complex and difficult to isolate. Recent advances in biomedical engineering (BME) and nanotechnology now permit unprecedented control over the physical and chemical properties of synthetic nanostructures, which can be designed to mimic the mechanisms of infection utilized by nanoscale pathogens such as viruses. The research objective of this proposal is therefore to engineer virus-mimicking nanostructures that will serve as tools to investigate specific hypotheses of how viruses can generate dysregulated immune responses. As engineering approaches to immunological questions become more commonplace, future students and researchers interested in highly specialized areas of immunology and virology must be encouraged to pursue careers in the field of BME. The educational objective of this proposal therefore implements a multi-pronged high school BME program that exposes students, as well as their parents, to the diverse opportunities made accessible by a career in BME. This proposal aims to expand BME into new specialized fields of biological science by directly demonstrating the benefits of engineering-based techniques and principles.A key need in the study of viral immunopathology is a customizable, in situ method to probe how specific viral structures, surface chemistries, and biodistributions contribute to virus-induced dysregulation of the immune system. The PI will rationally design a library of virus-mimicking polymeric nanocarriers (NCs) to investigate the basic biochemical and cellular mechanisms that trigger the model immunodysregulatory disorder hemophagocytic lymphohistiocytosis (HLH). HLH can be controllably induced in several mouse models following infection by the lymphocytic choriomeningitic virus (LCMV). Since the polymers are inert and do not elicit inflammatory responses, the NCs can be considered "blank slates" in which a diverse range of molecules and immunostimulants will be incorporated for controlled transport to and activation of specific immune cells. The essential inflammatory mechanisms that induce HLH are poorly understood, and so this system will be simplified by dividing the various inflammatory components within LCMV, such as its glycoprotein envelope or RNA, into separate NCs that mimic the biodistribution and mechanisms of intracellular degradation of the virus. NCs are assembled from block copolymers, and can be engineered into vesicular and filamentous nanostructures, which respectively target diverse and restricted subsets of inflammatory immune cells. Vesicles will probe hypothesized biochemical mechanisms responsible for HLH by inducing controlled systemic cytokine expression and effector T cell activation. The filaments will investigate the specific cellular role of plasmacytoid dendritic cells, which are an inflammatory immune cell population essential to immune responses against LCMV. Through the use of controlled synthetically induced infections, the key LCMV-related inflammatory mechanisms or combinations thereof responsible for HLH will be identified. This work will demonstrate the use of rationally designed nanomaterials to enhance the understanding of how specific inflammatory triggers contribute to immunopathology. Furthermore, data gathered in these studies will provide insight into essential design criteria required for eliciting specific and controlled immunological responses.