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.

doi:10.1101/2021.03.02.432977

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bioRxiv · 10.1101/2021.03.02.432977

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

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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): org.highwire.dtl.DTLVardef@a3c55aorg.highwire.dtl.DTLVardef@1f1c840org.highwire.dtl.DTLVardef@920bc7org.highwire.dtl.DTLVardef@43633e_HPS_FORMAT_FIGEXP M_FIG C_FIG

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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.. 2021-03-03. Neutralizing IFNL3 Autoantibodies in Severe COVID-19 Identified Using Molecular Indexing of Proteins by Self-Assembly. https://doi.org/10.1101/2021.03.02.432977

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