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

点击翻译按钮获取中文摘要

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.