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Multiplexed proteomics and imaging of resolving and lethal SARS-CoV-2 infection in the lung

View ORCID ProfileMarian Kalocsay, Zoltan Maliga, Ajit J. Nirmal, Robyn J. Eisert, Gary A. Bradshaw, Isaac H Solomon, Yu-An Chen, Roxanne J. Pelletier, Connor A. Jacobson, Julian Mintseris, Robert F. Padera, Amanda J. Martinot, Dan H. Barouch, Sandro Santagata, Peter K. Sorger
doi: https://doi.org/10.1101/2020.10.14.339952
Marian Kalocsay
1Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, MA 02115, USA
2Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA
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  • ORCID record for Marian Kalocsay
Zoltan Maliga
1Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, MA 02115, USA
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Ajit J. Nirmal
1Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, MA 02115, USA
3Department of Medical Oncology, Dana Farber Cancer Institute, Boston MA
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Robyn J. Eisert
1Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, MA 02115, USA
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Gary A. Bradshaw
1Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, MA 02115, USA
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Isaac H Solomon
4Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
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Yu-An Chen
1Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, MA 02115, USA
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Roxanne J. Pelletier
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Connor A. Jacobson
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Julian Mintseris
5Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
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Robert F. Padera
4Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
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Amanda J. Martinot
6Tufts University Cummings School of Veterinary Medicine, North Grafton, MA 01536, USA
7Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA
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Dan H. Barouch
7Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA
8Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA
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Sandro Santagata
1Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, MA 02115, USA
4Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
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Peter K. Sorger
1Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, MA 02115, USA
2Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA
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  • For correspondence: peter_sorger@hms.harvard.edu
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ABSTRACT

Normal tissue physiology and repair depends on communication with the immune system. Understanding this communication at the molecular level in intact tissue requires new methods. The consequences of SARS-CoV-2 infection, which can result in acute respiratory distress, thrombosis and death, has been studied primarily in accessible liquid specimens such as blood, sputum and bronchoalveolar lavage, all of which are peripheral to the primary site of infection in the lung. Here, we describe the combined use of multiplexed deep proteomics with multiplexed imaging to profile infection and its sequelae directly in fixed lung tissue specimens obtained from necropsy of infected animals and autopsy of human decedents. We characterize multiple steps in disease response from cytokine accumulation and protein phosphorylation to activation of receptors, changes in signaling pathways, and crosslinking of fibrin to form clots. Our data reveal significant differences between naturally resolving SARS-CoV-2 infection in rhesus macaques and lethal COVID-19 in humans. The approach we describe is broadly applicable to other tissues and diseases.

Summary Proteomics of infected tissue reveals differences in inflammatory and thrombotic responses between resolving and lethal COVID-19.

Competing Interest Statement

PKS is a member of the SAB or BOD member of Applied Biomath, RareCyte Inc., and Glencoe Software; PKS is also a member of the NanoString SAB. SS is a consultant for RareCyte Inc. The other authors declare no outside interests.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted October 15, 2020.
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Multiplexed proteomics and imaging of resolving and lethal SARS-CoV-2 infection in the lung
Marian Kalocsay, Zoltan Maliga, Ajit J. Nirmal, Robyn J. Eisert, Gary A. Bradshaw, Isaac H Solomon, Yu-An Chen, Roxanne J. Pelletier, Connor A. Jacobson, Julian Mintseris, Robert F. Padera, Amanda J. Martinot, Dan H. Barouch, Sandro Santagata, Peter K. Sorger
bioRxiv 2020.10.14.339952; doi: https://doi.org/10.1101/2020.10.14.339952
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Multiplexed proteomics and imaging of resolving and lethal SARS-CoV-2 infection in the lung
Marian Kalocsay, Zoltan Maliga, Ajit J. Nirmal, Robyn J. Eisert, Gary A. Bradshaw, Isaac H Solomon, Yu-An Chen, Roxanne J. Pelletier, Connor A. Jacobson, Julian Mintseris, Robert F. Padera, Amanda J. Martinot, Dan H. Barouch, Sandro Santagata, Peter K. Sorger
bioRxiv 2020.10.14.339952; doi: https://doi.org/10.1101/2020.10.14.339952

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