Engineering Human Vascular Beds to Study Endothelial Susceptibility to the Coronavirus Disease 2019

Project Overview

Identifying new treatments for critically ill patients with COVID-19 has proven difficult due to key differences between commonly used animal models and human biology, a key limitation to the field. SARS-CoV-2 enters cells via human angiotensin converting enzyme 2 (hACE2), which is expressed widely in varied human organs including the lung, heart, kidney, and vasculature. While transgenic mice expressing hACE2 in lung epithelium have been successfully infected with this virus, these animals lack the ACE2 receptor in their vasculature and do not show effects of SARS-CoV-2 infection in heart, spleen, or kidney. While other animal models such as macaques and hamsters show greater susceptibility to infection, these animal models do not display the coagulopathy or cytokine storm observed in human patients due to species differences in the ACE2 receptor. Furthermore, the human ACE2 receptor is polymorphic, with different SNP prevalence in different populations raising questions about whether any of these variants confers altered susceptibility. Thus, there is an urgent unmet need for infectable human tissue models to study the pathobiology of SARS-CoV-2.

In this work we take the first steps towards developing a human in vitro model of SARS-CoV-2 infection. Harnessing the virology expertise in the Biosciences and Biotechnology Division and the bioprinting capabilities of the Bioengineering and Advanced Fabrication Group, we created a viral infectable bioprinted in vitro human vasculature platform. This model offers unique opportunities to study why SARS-CoV-2 shows such clear preference for vascular system, and more generally, to understand how to counter the sequelae of this devastating disease. This work will establish the foundation needed to demonstrate the utility of Lawrence Livermore National Laboratory's (LLNL's) human in vitro platforms research area for responding to emerging threats.

Mission Impact

This project builds on two of LLNL's core competencies: Advanced Materials and Manufacturing as well as Bioscience and Bioengineering. This work uses the unique resources available at LLNL (functional vascular beds) to establish the feasibility of using engineered vascular beds to study susceptibility to SARS-CoV-2 and develop countermeasures against this disease. Vascular involvement is key to the pathogenesis of many emerging pathogens, and climate changes makes these diseases more likely to develop into pandemics. An infectable, physiologically relevant, human in vitro model is critical for understanding the pathogenesis of highly dangerous diseases and for developing effective countermeasures. This project aims to provide a unique platform for phenotypic analysis of the mutations associated with variant SARS-CoV-2 viruses that continue to emerge globally as the pandemic progresses. Importantly the platform established by this project may serve as a mechanism to predict the virulence potential associated with individual mutations and combinations of mutations that continue to emerge. We expect that the models developed in this work will have high relevance to LLNL's global security mission.