RAPID: Single-cell dissection of the cell types and mechanisms underlying SARS-CoV-2 entry in host cells via the ACE2 receptor and protease TMPRSS2

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The new coronavirus (SARS-CoV-2) is a global threat to worldwide economies and public health due to its highly contagious nature and rapid spread. To develop optimal strategies for containment and treatment of the coronavirus epidemic, it is critical to understand the cell types and biological mechanisms that mediate viral entry and propagation across the human population. Recent advancements in single-cell technologies now make it possible to measure the expression of genes at a cell-type resolution. This project aims to provide a comprehensive survey of the cell types used by SARS-CoV-2 for viral entry across the nasal airways, lung, and gut tissue and to understand physiological basis of how age, gender, and smoking history may predispose healthy individuals to infection. Identification of cells containing the two proteins known to mediate viral entry [the receptor protein angiotensin-converting enzyme-2 (ACE2) and the transmembrane serine protease 2 (TMPRSS2)] will elucidate the gene expression programs and signaling pathways associated with cells used by the novel coronavirus for host entry. Analysis of single-cell chromatin accessibility (scATAC-seq) data from the lung will identify the cell-type specific transcription factors and regulatory regions associated with these gene expression programs. This improved understanding of the signaling pathways, gene expression programs, and regulatory mechanisms of coronavirus infection of cells may lead to novel, patient- and region-specific therapeutic targets to combat the spread of SARS-CoV-2. The single-cell data will be made available for download, analysis, and visualization, thus providing a valuable resource to the scientific community.In addition to dissemination of the findings and contributing to potential treatment strategies for the control of coronavirus infection, the project will support the training and professional development of a data scientist and of a computational research associate.The catastrophic effects of the COVID-19 pandemic caused by the novel coronavirus (SARS-CoV-2) highlights an urgent need for improving scientific understanding of the underlying mechanisms of viral entry and propagation. SARS-CoV-2 uses the host ACE2 receptor protein and protease TMPRSS2 to gain cellular entry; however, what organs and cell types express these genes and how they interact with the host immune system remain obscure. Recent advancements in single-cell technologies now allow for the dissection of cell types and cell states at unprecedented resolution, which has led to groundbreaking discoveries in tissue biology. This project will integrate single-cell RNA-sequencing data across multiple individuals to assess how expression patterns of ACE2 and TMPRSS2 in the lung, the primary organ linked to coronavirus infection, are associated with an individual’s age, gender and smoking history. It will also provide a broader context of the distinct cell types in the lung and gut expressing ACE2 and TMPRSS2 and elucidate the gene expression programs and signaling pathways that are associated with viral entry in healthy individuals. Finally, analysis of single-cell chromatin accessibility data from different lung regions will identify the key transcription factors and regulatory mechanisms driving the expression programs related to viral entry. Taken together, this project will lead to a better understanding of coronavirus infection mechanisms. This RAPID award is made by the Physiological Mechanisms and Biomechanics Program and the Symbiosis, Defense, and Self-recognition Program in the BIO Division of Integrative Organismal Systems, using funds from the Coronavirus Aid, Relief, and Economic Security (CARES) Act.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.