Molecular Profiling of COVID-19 Autopsies Uncovers Novel Disease Mechanisms

Pujadas, Elisabet; Beaumont, Michael; Shah, Hardik; Schrode, Nadine; Francoeur, Nancy; Shroff, Sanjana; Bryce, Clare; Grimes, Zachary; Gregory, Jill; Donnelly, Ryan; Fowkes, Mary E.; Beaumont, Kristin G.; Sebra, Robert; Cordon-Cardo, Carlos

Current understanding of COVID-19 pathophysiology is limited by disease heterogeneity, complexity, and a paucity of studies assessing patient tissues with advanced molecular tools. Rapid autopsy tissues were evaluated using multi-scale RNASeq methods (bulk, single-nuclei, and spatial RNASeq next-generation sequencing) to provide unprecedented molecular resolution of COVID-19 induced damage. Comparison of infected/uninfected tissues revealed four major regulatory pathways. Effectors within these pathways could constitute novel therapeutic targets, including the complement receptor C3AR1, calcitonin receptor like receptor or decorin. Single-nuclei RNA sequencing of olfactory bulb and prefrontal cortex highlighted remarkable diversity of coronavirus receptors. ACE2 was rarely expressed, while BSG showed diffuse expression, and ANPEP was associated with vascular/mesenchymal cell types. Comparison of lung and lymph node tissues from patients with different symptomatology (one died after a month-long hospitalization with multi-organ involvement, the other after a few days of respiratory symptoms) with digital spatial profiling resulted in distinct molecular phenotypes. Evaluation of COVID-19 rapid autopsy tissues with advanced molecular techniques can identify pathways and effectors, map diverse receptors at the single-cell level, and help dissect differences driving diverging clinical courses among individual patients. Extension of this approach to larger datasets will substantially advance the understanding of the mechanisms behind COVID-19 pathophysiology.