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:10.1101/2021.03.02.432977

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

bioRxiv [Preprint]. 2021 Mar 3:2021.03.02.432977. doi: 10.1101/2021.03.02.432977.

Authors

Joel J Credle¹, Jonathan Gunn¹, Puwanat Sangkhapreecha¹, Daniel R Monaco¹, Xuwen Alice Zheng¹, Hung-Ji Tsai², Azaan Wilbon¹, William R Morgenlander¹, Yi Dong³, Sahana Jayaraman¹, Lorenzo Tosi⁴, Biju Parekkadan⁴, Alan N Baer⁵, Mario Roederer⁶, Evan M Bloch⁷, Aaron A R Tobian⁷, Israel Zyskind⁸, Jonathan I Silverberg⁹, Avi Z Rosenberg¹⁰, Andrea L Cox¹¹, Tom Lloyd¹², Andrew L Mammen¹³, H Benjamin Larman¹

Affiliations

¹ Institute for Cell Engineering, Division of Immunology, Department of Pathology, Johns Hopkins University School of Medicine; Baltimore, MD, USA.
² Institute of Microbiology and Infection, School of Biosciences, University of Birmingham, Edgbaston; Birmingham, United Kingdom.
³ Center for Cell Dynamics and Department of Cell Biology, Johns Hopkins University School of Medicine; Baltimore, MD, USA.
⁴ Department of Biomedical Engineering, Rutgers University; Piscataway, NJ, USA.
⁵ Division of Rheumatology, Department of Medicine, Johns Hopkins University School of Medicine; Baltimore, MD, USA.
⁶ ImmunoTechnology Section, Vaccine Research Center, NIAID, NIH; Bethesda, MD, USA.
⁷ Division of Transfusion Medicine, Department of Pathology, Johns Hopkins University School of Medicine; Baltimore, MD, USA.
⁸ Department of Pediatrics, NYU Langone Medical Center, New York, NY and Maimonides Medical Center; Brooklyn, NY, USA.
⁹ Department of Dermatology, George Washington University School of Medicine and Health Sciences; Washington, DC, USA.
¹⁰ Division of Transfusion Medicine, Department of Pathology, Johns Hopkins University; Baltimore, MD, USA.
¹¹ Division of Infectious Diseases, Department of Medicine, Johns Hopkins University; Baltimore, MD, USA.
¹² Departments of Neurology and Neuroscience, Johns Hopkins University School of Medicine; Baltimore, MD, USA.
¹³ Muscle 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.

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.

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Abstract

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