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Neutralizing IFNL3 Autoantibodies in Severe COVID-19 Identified Using Molecular Indexing of Proteins by Self-Assembly

Joel J. Credle, Jonathan Gunn, Puwanat Sangkhapreecha, Daniel R. Monaco, Xuwen Alice Zheng, Hung-Ji Tsai, Azaan Wilbon, William R. Morgenlander, Yi Dong, Sahana Jayaraman, Lorenzo Tosi, Biju Parekkadan, Alan N. Baer, Mario Roederer, Evan M. Bloch, Aaron A. R. Tobian, Israel Zyskind, Jonathan I. Silverberg, Avi Z. Rosenberg, Andrea L. Cox, Tom Lloyd, Andrew L. Mammen, H. Benjamin Larman
doi: https://doi.org/10.1101/2021.03.02.432977
Joel J. Credle
1Institute for Cell Engineering, Division of Immunology, Department of Pathology, Johns Hopkins University School of Medicine; Baltimore, MD, USA
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Jonathan Gunn
1Institute for Cell Engineering, Division of Immunology, Department of Pathology, Johns Hopkins University School of Medicine; Baltimore, MD, USA
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Puwanat Sangkhapreecha
1Institute for Cell Engineering, Division of Immunology, Department of Pathology, Johns Hopkins University School of Medicine; Baltimore, MD, USA
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Daniel R. Monaco
1Institute for Cell Engineering, Division of Immunology, Department of Pathology, Johns Hopkins University School of Medicine; Baltimore, MD, USA
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Xuwen Alice Zheng
1Institute for Cell Engineering, Division of Immunology, Department of Pathology, Johns Hopkins University School of Medicine; Baltimore, MD, USA
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Hung-Ji Tsai
2Institute of Microbiology and Infection, School of Biosciences, University of Birmingham, Edgbaston; Birmingham, United Kingdom
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Azaan Wilbon
1Institute for Cell Engineering, Division of Immunology, Department of Pathology, Johns Hopkins University School of Medicine; Baltimore, MD, USA
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William R. Morgenlander
1Institute for Cell Engineering, Division of Immunology, Department of Pathology, Johns Hopkins University School of Medicine; Baltimore, MD, USA
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Yi Dong
3Center for Cell Dynamics and Department of Cell Biology, Johns Hopkins University School of Medicine; Baltimore, MD, USA
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Sahana Jayaraman
1Institute for Cell Engineering, Division of Immunology, Department of Pathology, Johns Hopkins University School of Medicine; Baltimore, MD, USA
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Lorenzo Tosi
4Department of Biomedical Engineering, Rutgers University; Piscataway, NJ, USA
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Biju Parekkadan
4Department of Biomedical Engineering, Rutgers University; Piscataway, NJ, USA
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Alan N. Baer
5Division of Rheumatology, Department of Medicine, Johns Hopkins University School of Medicine; Baltimore, MD, USA
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Mario Roederer
6ImmunoTechnology Section, Vaccine Research Center, NIAID, NIH; Bethesda, MD, USA
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Evan M. Bloch
7Division of Transfusion Medicine, Department of Pathology, Johns Hopkins University School of Medicine; Baltimore, MD, USA
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Aaron A. R. Tobian
7Division of Transfusion Medicine, Department of Pathology, Johns Hopkins University School of Medicine; Baltimore, MD, USA
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Israel Zyskind
8Department of Pediatrics, NYU Langone Medical Center, New York, NY and Maimonides Medical Center; Brooklyn, NY, USA
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Jonathan I. Silverberg
9Department of Dermatology, George Washington University School of Medicine and Health Sciences; Washington, DC, USA
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Avi Z. Rosenberg
10Division of Transfusion Medicine, Department of Pathology, Johns Hopkins University; Baltimore, MD, USA
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Andrea L. Cox
11Division of Infectious Diseases, Department of Medicine, Johns Hopkins University; Baltimore, MD, USA
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Tom Lloyd
12Departments of Neurology and Neuroscience, Johns Hopkins University School of Medicine; Baltimore, MD, USA
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Andrew L. Mammen
13Muscle Disease Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH; Bethesda, MD, USA and Departments of Neurology and Medicine, Johns Hopkins University School of Medicine; Baltimore, MD, USA
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H. Benjamin Larman
1Institute for Cell Engineering, Division of Immunology, Department of Pathology, Johns Hopkins University School of Medicine; Baltimore, MD, USA
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  • For correspondence: hlarman1@jhu.edu
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Abstract

Unbiased antibody profiling can identify the targets of an immune reaction. A number of likely pathogenic autoreactive antibodies have been associated with life-threatening SARS-CoV-2 infection; yet, many additional autoantibodies likely remain unknown. Here we present Molecular Indexing of Proteins by Self Assembly (MIPSA), a technique that produces ORFeome-scale libraries of proteins covalently coupled to uniquely identifying DNA barcodes for analysis by sequencing. We used MIPSA to profile circulating autoantibodies from 55 patients with severe COVID-19 against 11,076 DNA-barcoded proteins of the human ORFeome library. MIPSA identified previously known autoreactivities, and also detected undescribed neutralizing interferon lambda 3 (IFN-λ3) autoantibodies. At-risk individuals with anti-IFN-λ3 antibodies may benefit from interferon supplementation therapies, such as those currently undergoing clinical evaluation.

One-Sentence Summary Molecular Indexing of Proteins by Self Assembly (MIPSA) identifies neutralizing IFNL3 autoantibodies in patients with severe COVID-19.

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Competing Interest Statement

HBL, JJC and JG are inventors on a patent application filed by Johns Hopkins University that covers the MIPSA technology. HBL is a founder of Portal Bioscience, Alchemab and ImmuneID, and is an advisor to CDI Laboratories and TScan Therapeutics.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Neutralizing IFNL3 Autoantibodies in Severe COVID-19 Identified Using Molecular Indexing of Proteins by Self-Assembly
Joel J. Credle, Jonathan Gunn, Puwanat Sangkhapreecha, Daniel R. Monaco, Xuwen Alice Zheng, Hung-Ji Tsai, Azaan Wilbon, William R. Morgenlander, Yi Dong, Sahana Jayaraman, Lorenzo Tosi, Biju Parekkadan, Alan N. Baer, Mario Roederer, Evan M. Bloch, Aaron A. R. Tobian, Israel Zyskind, Jonathan I. Silverberg, Avi Z. Rosenberg, Andrea L. Cox, Tom Lloyd, Andrew L. Mammen, H. Benjamin Larman
bioRxiv 2021.03.02.432977; doi: https://doi.org/10.1101/2021.03.02.432977
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Neutralizing IFNL3 Autoantibodies in Severe COVID-19 Identified Using Molecular Indexing of Proteins by Self-Assembly
Joel J. Credle, Jonathan Gunn, Puwanat Sangkhapreecha, Daniel R. Monaco, Xuwen Alice Zheng, Hung-Ji Tsai, Azaan Wilbon, William R. Morgenlander, Yi Dong, Sahana Jayaraman, Lorenzo Tosi, Biju Parekkadan, Alan N. Baer, Mario Roederer, Evan M. Bloch, Aaron A. R. Tobian, Israel Zyskind, Jonathan I. Silverberg, Avi Z. Rosenberg, Andrea L. Cox, Tom Lloyd, Andrew L. Mammen, H. Benjamin Larman
bioRxiv 2021.03.02.432977; doi: https://doi.org/10.1101/2021.03.02.432977

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