COVID-19 is a severe disease that has caused >1 million deaths in under one year. As this disease is novel, the molecular and cellular underpinnings of the progressive tissue injury are poorly understood, as is the role of direct versus indirect viral-induced injury. This study compared spatially-resolved gene expression in fixed lung tissue from autopsies of COVID-19 patients with high and low viral loads to those who suffered from other respiratory diseases – flu or non-viral acute respiratory distress syndrome (ARDS) – and normal lung tissue. We used the DreamPrep™ NAP workstation to extract RNA and DNA to profile 735 COVID-19 patients. Using normal samples as a reference, there was an enrichment of genes involved in antigen presentation and interferon response in high and low viral load patients. Between COVID-19 cohorts, there was an overall upregulation of individual interferon-stimulating genes in COVID high patients, and an increase in collagen genes found in COVID-low patients. Pathway analysis revealed enrichment in interferon alpha/beta and gamma signaling in COVID-19 samples compared to
