COVID-19 and the Role of the Immune System in Cardiac Function and Pathology

冠状病毒病2019(新冠肺炎)已成为2020年全球突发公共卫生事件。虽然它主要针对肺部，但也会影响心脏。事实上，新冠肺炎损害了心脏产生足够力量将含氧血液输送到全身的能力。这可能会导致心肌异常和心力衰竭。然而，导致这些并发症的机制仍不清楚。一个可能的原因是缺氧，这是心肌可用氧减少，再加上过度刺激的免疫系统。因此，这项工作的目的是开发一种新型的免疫心脏芯片，以阐明心脏生物力学与缺氧和免疫系统过度活跃的联合痛苦之间的关系。如果成功，这个系统将导致对心脏和免疫细胞之间相互作用的更基本的理解，以及它们的环境因素。这一结果将适用于健康的心功能，也适用于临床上看到的与新冠肺炎相关的心脏并发症。这种理解将引发对潜在免疫靶点和新疗法的讨论，这些疗法可能会在新冠肺炎感染期间和之后保护心脏的机械功能。该项目还将通过外展计划提高本科生和高中生对科学研究的兴趣。具体地说，这些学生将在新冠肺炎研究和心脏免疫工程的接口上从事科学研究。已知，在缺氧性心肌损伤期间，免疫细胞，主要是巨噬细胞，被从循环中招募来参与炎症和修复。新冠肺炎诱导的细胞因子风暴导致巨噬细胞过度激活，进一步增加了破译体内心脏免疫动力学的复杂性。研究小组将在各种培养条件下研究心肌细胞的表型(形态和结构)和功能(收缩和电生理)。该项目将产生第一个包含免疫成分和氧气梯度发生器的心脏芯片。这一变革性的平台将能够模拟对新冠肺炎条件(静默缺氧、微血管功能障碍导致的缺血和全身性炎症)的多系统反应，并促进对健康和病理组织中心肌细胞-巨噬细胞相互作用和相关心脏力学的基础理解。这一平台与啮齿动物和人类细胞株的兼容性将阐明啮齿动物和人类心脏力学之间的物种差异，提高我们对啮齿动物心脏模型的理解。该研究小组将量化巨噬细胞的募集和迁移，以应对缺氧的心脏组织和高炎症条件，以及因巨噬细胞的存在和受损心肌细胞的吞噬而导致的心肌细胞功能的变化。这些研究将阐明正常和新冠肺炎影响的心脏应激产生的动力学，并为进一步测试新冠肺炎诱导的心脏损伤的潜在机制和干预措施提供基础性资源。该奖项反映了美国国家科学基金会的法定使命，并已通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

The coronavirus disease 2019 (COVID-19) has become a worldwide public health emergency in 2020. Although it primarily targets the lungs, it also affects the heart. Indeed, COVID-19 compromises the heart’s ability to generate sufficient force to pump oxygenated blood throughout the body. This can lead to heart muscle abnormalities and heart failure. However, the mechanisms that cause these complications remain unclear. One possible cause is hypoxia, which is decreased available oxygen for the heart muscle, combined with an overstimulated immune system. Thus, the objective of this work is to develop a novel immuno-heart chip to elucidate the relationship between cardiac biomechanics and the combined affliction of hypoxia and an overactive immune system. If successful, this system will lead to a greater fundamental understanding of the reciprocal interactions between heart and immune cells, in conjunction with their environmental factors. The results will be applicable to healthy cardiac function and also to the COVID-19-related cardiac complications seen clinically. This understanding will spark conversation towards potential immune targets and novel therapies that may preserve the heart’s mechanical function during and after COVID-19 infection. The project will also promote interest in scientific research among undergraduate and high-school students through outreach programs. Specifically, these students will be engaged with the scientific study at the interface of COVID-19 research and cardio-immune engineering. It is known that immune cells, predominantly macrophages, are recruited from circulation to participate in inflammation and healing during hypoxic myocardial damage. Overactivation of macrophages by COVID-19-induced cytokine storm adds further complexity to deciphering cardio-immune dynamics in vivo. The research team will investigate cardiomyocyte phenotype (morphology and architecture) and function (contractility and electrophysiology) in a variety of culture conditions. This project will result in the first heart-chip to incorporate an immune component and oxygen gradient generator. This transformative platform will be able to simulate a multi-system response to COVID-19 conditions (silent hypoxia, microvascular dysfunction induced ischemia, and systemic hyperinflammation) and advance fundamental understanding of cardiomyocyte-macrophage interactions and the associated cardiac mechanics in healthy and pathological tissues. The compatibility of this platform with both rodent and human cell lines will elucidate species differences between rodent and human cardiac mechanics, improving our understanding of the rodent cardiac model. The research team will quantify macrophage recruitment and migration in response to hypoxic cardiac tissue and hyperinflammatory conditions and changes in cardiomyocyte function in response to macrophage presence and efferocytosis of injured cardiomyocytes. These studies will elucidate the dynamics of normal and COVID-19-affected cardiac stress generation and provide a foundational resource for further testing of potential mechanisms of and interventions for COVID-19-induced induced cardiac injury.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.