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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

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AbstractUnbiased 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 SummaryMolecular Indexing of Proteins by Self Assembly (MIPSA) identifies neutralizing IFNL3 autoantibodies in patients with severe COVID-19.Graphical Abstract