Integrative imaging reveals SARS-CoV-2 induced reshaping of subcellular morphologies

Cortese, Mirko; Lee, Ji-Young; Cerikan, Berati; Neufeldt, Christopher J.; Oorschot, Viola M.J.; Köhrer, Sebastian; Hennies, Julian; Schieber, Nicole L.; Ronchi, Paolo; Mizzon, Giulia; Brey, Inés Romero; Santarella-Mellwig, Rachel; Schorb, Martin; Boermel, Mandy; Mocaer, Karel; Beckwith, Marianne S.; Templin, Rachel M.; Gross, Viktoriia; Pape, Constantin; Tischer, Christian; Frankish, Jamie; Horvat, Natalie K.; Laketa, Vibor; Stanifer, Megan; Boulant, Steeve; Ruggieri, Alessia; Chatel-Chaix, Laurent; Schwab, Yannick; Bartenschlager, Ralf

Pathogenesis induced by SARS-CoV-2 is thought to result from both an inflammation dominated cytokine response and virus-induced cell perturbation causing cell death. Here, we employ an integrative imaging analysis to determine morphological organelle alterations induced in SARS-CoV-2 infected human lung epithelial cells. We report 3D electron microscopy reconstructions of whole-cells and subcellular compartments, revealing extensive fragmentation of the Golgi apparatus, alteration of the mitochondrial network and recruitment of peroxisomes to viral replication organelles formed by clusters of double-membrane vesicles (DMVs). These are tethered to the endoplasmic reticulum, providing insights into DMV biogenesis and spatial coordination of SARS-CoV-2 replication. Live cell imaging combined with an infection sensor reveals profound remodeling of cytoskeleton elements. Pharmacological inhibition of their dynamics suppresses SARS-CoV-2 replication. We thus report insights into virus-induced cytopathic effects, and provide alongside a comprehensive publicly available repository of 3D data-sets of SARS-CoV-2 infected cells for download and smooth online visualization.