Published on Wed Mar 03 2021

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

Credle, J. J., Gunn, J., Sangkhapreecha, P., Monaco, D. R., Zheng, X. A., Tsai, H.-J., Wilbon, A., Morgenlander, W. R., Dong, Y., Jayaraman, S., Tosi, L., Parekkadan, B., Baer, A. N., Roederer, M., Bloch, E. M., Tobian, A. A. R., Zyskind, I., Silverberg, J. I., Rosenberg, A. Z., Cox, A. L., Lloyd, T., Mammen, A. L., Larman, H. B.

Molecular Indexing of Proteins by Self Assembly (MIPSA) identifies neutralizing IFNL3 autoantibodies in patients with severe COVID-19. MIPSA identified previously known autoreactivities, and also detected undescribed neutralizing interferon Lambda 3 (IFN-{lambda}3) auto Antibodies.

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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-{lambda}3) autoantibodies. At-risk individuals with anti-IFN-{lambda}3 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 O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=144 SRC="FIGDIR/small/432977v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): [email protected]@[email protected][email protected]_HPS_FORMAT_FIGEXP M_FIG C_FIG