Unbiased discovery of autoantibodies associated with severe COVID-19 via genome-scale self-assembled DNA-barcoded protein libraries

Joel J. Credle, Institute for Cell Engineering, Division of Immunology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Jonathan Gunn, Institute for Cell Engineering, Division of Immunology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Puwanat Sangkhapreecha, Institute for Cell Engineering, Division of Immunology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Daniel R. Monaco, Institute for Cell Engineering, Division of Immunology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Xuwen Alice Zheng, Institute for Cell Engineering, Division of Immunology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Hung-Ji Tsai, Institute of Microbiology and Infection, School of Biosciences, University of Birmingham, Edgbaston, Birmingham, UK.
Azaan Wilbon, Institute for Cell Engineering, Division of Immunology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
William R. Morgenlander, Institute for Cell Engineering, Division of Immunology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Andre Rastegar, Institute for Cell Engineering, Division of Immunology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Yi Dong, Center for Cell Dynamics and Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Sahana Jayaraman, Institute for Cell Engineering, Division of Immunology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Lorenzo Tosi, Department of Biomedical Engineering, Rutgers University, Piscataway, NJ, USA.
Biju Parekkadan, Department of Biomedical Engineering, Rutgers University, Piscataway, NJ, USA.
Alan N. Baer, Division of Rheumatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Mario Roederer, ImmunoTechnology Section, Vaccine Research Center, NIAID, NIH, Bethesda, MD, USA.
Evan M. Bloch, Division of Transfusion Medicine, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Aaron A. Tobian, Division of Transfusion Medicine, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Israel Zyskind, Department of Pediatrics, NYU Langone Medical Center, New York City, NY, USA.
Jonathan I. Silverberg, Department of Dermatology, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
Avi Z. Rosenberg, Division of Kidney-Urologic Pathology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Andrea L. Cox, Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Tom Lloyd, Department of Neurology and Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Andrew L. Mammen, Department of Neurology and Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
H Benjamin Larman, Institute for Cell Engineering, Division of Immunology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. hlarman1@jhmi.edu.

Document Type

Journal Article

Publication Date

8-1-2022

Journal

Nature biomedical engineering

Volume

6

Issue

8

DOI

10.1038/s41551-022-00925-y

Abstract

Pathogenic autoreactive antibodies that may be associated with life-threatening coronavirus disease 2019 (COVID-19) remain to be identified. Here, we show that self-assembled genome-scale libraries of full-length proteins covalently coupled to unique DNA barcodes for analysis by sequencing can be used for the unbiased identification of autoreactive antibodies in plasma samples. By screening 11,076 DNA-barcoded proteins expressed from a sequence-verified human ORFeome library, the method, which we named MIPSA (for Molecular Indexing of Proteins by Self-Assembly), allowed us to detect circulating neutralizing type-I and type-III interferon (IFN) autoantibodies in five plasma samples from 55 patients with life-threatening COVID-19. In addition to identifying neutralizing type-I IFN-α and IFN-ω autoantibodies and other previously known autoreactive antibodies in patient plasma, MIPSA enabled the detection of as yet unidentified neutralizing type-III anti-IFN-λ3 autoantibodies that were not seen in healthy plasma samples or in convalescent plasma from ten non-hospitalized individuals with COVID-19. The low cost and simple workflow of MIPSA will facilitate unbiased high-throughput analyses of protein-antibody, protein-protein and protein-small-molecule interactions.

Department

Dermatology

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