Decoding the cellular mechanisms of COVID-19 severe disease susceptibility in patients with chronic respiratory disease

PROJECT SUMMARY The new coronavirus (SARS-CoV-2) and associated disease (COVID-19) is a global threat to worldwide economies and public health due to its highly contagious nature and rapid spread. To develop optimal strategies for treatment of COVID-19, it is critical to understand the cell types and molecular mechanisms that mediate coronavirus infection, tissue propagation, and host immune response. As recently reported, both SARS-CoV and SARS-CoV-2 use the host ACE2 receptor protein and protease TMPRSS2 to gain cellular entry. High-throughput single-cell RNA-sequencing (scRNA-seq) and Assay for Transposase-Accessible Chromatin (scATAC-seq) now allow us to interrogate cell types and cell states at unprecedented resolution, which has led to groundbreaking discoveries in lung tissue biology, including our lab's and the Human Cell Atlas recent survey of nasal and lung epithelial cell types that co-express ACE2 and TMPRSS2 consistent with disease phenotype. It has been reported that individuals suffering from chronic respiratory diseases are more susceptible to COVID-19 severe disease. We propose to leverage our expertise in lung biology, single-cell analysis, and unique access to lung tissue at Mount Sinai from COVID-19 patients with chronic respiratory disease comorbidities to define the cell types and regulatory mechanisms that mediate COVID-19 disease susceptibility due to SARS-CoV-2 infection, propagation and interplay with the host immune response. Towards this goal, we will perform scRNA-seq, scATAC-seq, and spatial transcriptomic sequencing of multiple infected and non-infected lung regions in 25-30 patients with COVID-19 and chronic obstructive pulmonary disease comorbidity following autopsy. The single-cell resolution data will allow us to characterize the repertoire of SARS-CoV-2 infected cell and surrounding stromal and immune microenvironment and how they contribute to developing COVID-19 severe disease. Analysis of scATAC-seq data from matched lung regions will identify the key transcription factors and regulatory mechanisms driving the expression programs related to viral infection, host immune response, and severe disease susceptibility. Finally, integration of ligand-receptor pair expression and spatial transcriptomics information will elucidate at greater resolution and scale how cell- cell interactions and tissue pathology are altered after coronavirus infection. Single-cell characterization of the cell types, immune response, and regulatory mechanisms of infection will improve our understanding of virus- host interactions and COVID-19 severe disease susceptibility in patients with chronic respiratory disease. This will, in turn, provide mechanistic insight towards discovering new therapeutic targets that specifically benefit COVID-19 patients with pre-existing respiratory conditions.