A single-cell and spatial atlas of autopsy tissues reveals pathology and cellular targets of SARS-CoV-2
Authors: Delorey Toni M. , Ziegler Carly G. K. , Heimberg Graham , Normand Rachelly , Yang Yiming , Segerstolpe Asa , Abbondanza Domenic , Fleming Stephen J. , Subramanian Ayshwarya , Montoro Daniel T. , Jagadeesh Karthik A. , Dey Kushal K. , Sen Pritha , Slyper Michal , Pita-Juárez Yered H. , Phillips Devan , Bloom-Ackerman Zohar , Barkas Nick , Ganna Andrea , Gomez James , Normandin Erica , Naderi Pourya , Popov Yury V. , Raju Siddharth S. , Niezen Sebastian , Tsai Linus T.-Y. , Siddle Katherine J. , Sud Malika , Tran Victoria M. , Vellarikkal Shamsudheen K. , Amir-Zilberstein Liat , Atri Deepak S. , Beechem Joseph , Brook Olga R. , Chen Jonathan , Divakar Prajan , Dorceus Phylicia , Engreitz Jesse M. , Essene Adam , Fitzgerald Donna M. , Fropf Robin , Gazal Steven , Gould Joshua , Grzyb John , Harvey Tyler , Hecht Jonathan , Hether Tyler , Jane-Valbuena Judit , Leney-Greene Michael , Ma Hui , McCabe Cristin , McLoughlin Daniel E. , Miller Eric M. , Muus Christoph , Niemi Mari , Padera Robert , Pan Liuliu , Pant Deepti , Pe’er Carmel , Pfiffner-Borges Jenna , Pinto Christopher J. , Plaisted Jacob , Reeves Jason , Ross Marty , Rudy Melissa , Rueckert Erroll H. , Siciliano Michelle , Sturm Alexander , Todres Ellen , Waghray Avinash , Warren Sarah , Zhang Shuting , Zollinger Daniel R. , Cosimi Lisa , Gupta Rajat M. , Hacohen Nir , Hide Winston , Price Alkes L. , Rajagopal Jayaraj , Tata Purushothama Rao , Riedel Stefan , Szabo Gyongyi , Tickle Timothy L. , Hung Deborah , Sabeti Pardis C. , Novak Richard , Rogers Robert , Ingber Donald E. , Gordon Jiang Z. , Juric Dejan , Babadi Mehrtash , Farhi Samouil L. , Stone James R. , Vlachos Ioannis S. , Solomon Isaac H. , Ashenberg Orr , Porter Caroline B.M. , Li Bo , Shalek Alex K. , Villani Alexandra-Chloé , Rozenblatt-Rosen Orit , Regev Aviv 
Published: February 2021

The SARS-CoV-2 pandemic has caused over 1 million deaths globally, mostly due to acute lung injury and acute respiratory distress syndrome, or direct complications resulting in multiple-organ failures. Little is known about the host tissue immune and cellular responses associated with COVID-19 infection, symptoms, and lethality. To address this, we collected tissues from 11 organs during the clinical autopsy of 17 individuals who succumbed to COVID-19, resulting in a tissue bank of approximately 420 specimens. We generated comprehensive cellular maps capturing COVID-19 biology related to patients’ demise through single-cell and single-nucleus RNA-Seq of lung, kidney, liver and heart tissues, and further contextualized our findings through spatial RNA profiling of distinct lung regions. We developed a computational framework that incorporates removal of ambient RNA and automated cell type annotation to facilitate comparison with other healthy and diseased tissue atlases. In the lung, we uncovered significantly altered transcriptional programs within the epithelial, immune, and stromal compartments and cell intrinsic changes in multiple cell types relative to lung tissue from healthy controls. We observed evidence of: alveolar type 2 (AT2) differentiation replacing depleted alveolar type 1 (AT1) lung epithelial cells, as previously seen in fibrosis; a concomitant increase in myofibroblasts reflective of defective tissue repair; and, putative TP63+intrapulmonary basal-like progenitor (IPBLP) cells, similar to cells identified in H1N1 influenza, that may serve as an emergency cellular reserve for severely damaged alveoli. Together, these findings suggest the activation and failure of multiple avenues for regeneration of the epithelium in these terminal lungs. SARS-CoV-2 RNA reads were enriched in lung mononuclear phagocytic cells and endothelial cells, and these cells expressed distinct host response transcriptional programs. We corroborated the compositional and transcriptional changes in lung tissue through spatial analysis of RNA profilesin situand distinguished unique tissue host responses between regions with and without viral RNA, and in COVID-19 donor tissues relative to healthy lung. Finally, we analyzed genetic regions implicated in COVID-19 GWAS with transcriptomic data to implicate specific cell types and genes associated with disease severity. Overall, our COVID-19 cell atlas is a foundational dataset to better understand the biological impact of SARS-CoV-2 infection across the human body and empowers the identification of new therapeutic interventions and prevention strategies.