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

Credle, Joel J.; Gunn, Jonathan; Sangkhapreecha, Puwanat; Monaco, Daniel R.; Zheng, Xuwen Alice; Tsai, Hung-Ji; Wilbon, Azaan; Morgenlander, William R.; Dong, Yi; Jayaraman, Sahana; Tosi, Lorenzo; Parekkadan, Biju; Baer, Alan N.; Roederer, Mario; Bloch, Evan M.; Tobian, Aaron A. R.; Zyskind, Israel; Silverberg, Jonathan I.; Rosenberg, Avi Z.; Cox, Andrea L.; Lloyd, Tom; Mammen, Andrew L.; Larman, H. Benjamin

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.