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A single-cell and spatial atlas of autopsy tissues reveals pathology and cellular targets of SARS-CoV-2.
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.
Affiliation
  • Delorey TM; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA, USA.
  • Ziegler CGK; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Heimberg G; Program in Health Sciences & Technology, Harvard Medical School & Massachusetts Institute of Technology, Boston, MA 02115, USA.
  • Normand R; Institute for Medical Engineering & Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • Yang Y; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • Segerstolpe A; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA.
  • Abbondanza D; Harvard Graduate Program in Biophysics, Harvard University, Cambridge, MA 02138, USA.
  • Fleming SJ; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA, USA.
  • Subramanian A; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Montoro DT; Center for Immunology and Inflammatory Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
  • Jagadeesh KA; Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
  • Dey KK; Harvard Medical School, Boston, MA 02115, USA.
  • Sen P; Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • Slyper M; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA, USA.
  • Pita-Juárez YH; Center for Immunology and Inflammatory Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
  • Phillips D; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA, USA.
  • Bloom-Ackerman Z; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA, USA.
  • Barkas N; Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142.
  • Ganna A; Precision Cardiology Laboratory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Gomez J; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA, USA.
  • Normandin E; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Naderi P; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA, USA.
  • Popov YV; Department of Epidemiology, Harvard School of Public Health.
  • Raju SS; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Niezen S; Center for Immunology and Inflammatory Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
  • Tsai LT; Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
  • Siddle KJ; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
  • Sud M; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA, USA.
  • Tran VM; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Vellarikkal SK; Harvard Medical School, Boston, MA 02115, USA.
  • Amir-Zilberstein L; Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
  • Atri DS; Harvard Medical School Initiative for RNA Medicine, Boston, MA 02115, USA.
  • Beechem J; Cancer Research Institute, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
  • Brook OR; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA, USA.
  • Chen J; Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Divakar P; Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142.
  • Dorceus P; Institute for Molecular Medicine Finland, Helsinki, Finland.
  • Engreitz JM; Analytical & Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • Essene A; Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Fitzgerald DM; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Fropf R; Harvard Medical School, Boston, MA 02115, USA.
  • Gazal S; Harvard Medical School, Boston, MA 02115, USA.
  • Gould J; Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
  • Grzyb J; Harvard Medical School Initiative for RNA Medicine, Boston, MA 02115, USA.
  • Harvey T; Harvard Medical School, Boston, MA 02115, USA.
  • Hecht J; Department of Medicine, Beth Israel Deaconess Medical Center, MA 02115, USA.
  • Hether T; Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
  • Jane-Valbuena J; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • Leney-Greene M; Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
  • Ma H; FAS Center for Systems Biology, Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA 02138, USA.
bioRxiv ; 2021 Feb 25.
Article in En | MEDLINE | ID: mdl-33655247
ABSTRACT
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 profiles in situ and 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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Type of study: Prognostic_studies Language: En Journal: BioRxiv Year: 2021 Document type: Article Affiliation country: Estados Unidos
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Full text: 1 Collection: 01-internacional Database: MEDLINE Type of study: Prognostic_studies Language: En Journal: BioRxiv Year: 2021 Document type: Article Affiliation country: Estados Unidos