COVID-19, classified as a viral pandemic on 3/11/2020, has rapidly spread globally and caused over 250,000 deaths worldwide by 5/5/2020. COVID-19 symptoms range from mild fever and sore throat, to acute respiratory distress syndrome (ARDS) and death. SARS-CoV-2, the virus that causes COVID-19, avoids detection by the body’s immune system and enters the epithelial cells lining the airways, where it replicates and recruits a flood of immune cells, leading to what is called a “cytokine storm.” This “storm” can inflame the tissues surrounding the infection and eventually shut down breathing entirely. To date, basic studies on virus entry, propagation, and drug testing use non-human, non-lung models, like the Vero African green monkey kidney cell line, which severely limits efforts to understand COVID-19 disease and develop therapies. To address this problem, the objective of this project is to develop a platform emulating the human lung environment to study how SARS-CoV-2 interacts with the lung epithelial cells and with immune cells recruited to the lung and how therapies may modulate these interactions to benefit patients. The approach makes use of a model that the investigators have validated for studies of Cystic Fibrosis and Acute Respiratory Distress Syndrome (ARDS). The model features cultures of human airway epithelium grown on scaffolds that enable virus exposure, immune cell attraction and administration of existing drugs being considered for COVID-19 treatment. The platform developed will open broad opportunities for research not only on SARS-CoV-2, but also on other conditions (e.g., respiratory viruses or environmental exposures) that impact human lung physiology and health.The objective of this project is to engineer and validate a novel technological platform emulating the human lung environment to study how SARS-CoV-2, the causative agent of COVID-19 disease, interacts with epithelial cells lining the lung and with leukocytes recruited to the lung in response to infection, and how therapies may modulate these interactions to benefit patients. Unique features of the life-like platform include: (1) the use of human airway cells (both alveolar and bronchial epithelium) at ALI (Air-Liquid Interface) to propagate the virus over several days which enables the system to acquire the receptors and pathways relevant to human lung infections; (2) the use of human blood leukocytes transmigrated at chosen timepoints during infection, which is a key advantage over in vitro setups that use blood in lieu of lung leukocytes or animal models; and (3) due to the inclusion of all key components in the disease (virus, epithelium, leukocytes), the ability to assess drugs for their effects on the whole system, regardless of their primary target. The underlying hypothesis of the project is that SARS-CoV-2 causes pathology upon infection of the human lung by delaying interferon signaling, allowing the virus to infect monocytes, after which a breakdown in innate control occurs resulting in a cytokine storm, and in turn, overwhelming neutrophil recruitment and ARDS (Acute Respiratory Distress Syndrome). The research is organized under two Aims: (1) Determine the ability of the SARS-CoV-2 virus to enter and replicate in human lung epithelial cells and lung-recruited leukocytes and (2) Identify key pathways in human lung epithelial cells and lung-recruited leukocytes that can be modulated by existing drugs to prevent disease, e.g., remdesivir, baricitinib, anti-lL-6, anakinra, as well as a combination of remdesivir and baricitinibs which should impact both the virus and the inflammation.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.