Unbiased discovery of autoantibodies associated with severe COVID-19 via genome-scale self-assembled DNA-barcoded protein libraries
Nature biomedical engineering
Pathogenic autoreactive antibodies that may be associated with life-threatening coronavirus disease 2019 (COVID-19) remain to be identified. Here, we show that self-assembled genome-scale libraries of full-length proteins covalently coupled to unique DNA barcodes for analysis by sequencing can be used for the unbiased identification of autoreactive antibodies in plasma samples. By screening 11,076 DNA-barcoded proteins expressed from a sequence-verified human ORFeome library, the method, which we named MIPSA (for Molecular Indexing of Proteins by Self-Assembly), allowed us to detect circulating neutralizing type-I and type-III interferon (IFN) autoantibodies in five plasma samples from 55 patients with life-threatening COVID-19. In addition to identifying neutralizing type-I IFN-α and IFN-ω autoantibodies and other previously known autoreactive antibodies in patient plasma, MIPSA enabled the detection of as yet unidentified neutralizing type-III anti-IFN-λ3 autoantibodies that were not seen in healthy plasma samples or in convalescent plasma from ten non-hospitalized individuals with COVID-19. The low cost and simple workflow of MIPSA will facilitate unbiased high-throughput analyses of protein-antibody, protein-protein and protein-small-molecule interactions.
Credle, Joel J.; Gunn, Jonathan; Sangkhapreecha, Puwanat; Monaco, Daniel R.; Zheng, Xuwen Alice; Tsai, Hung-Ji; Wilbon, Azaan; Morgenlander, William R.; Rastegar, Andre; Dong, Yi; Jayaraman, Sahana; Tosi, Lorenzo; Parekkadan, Biju; Baer, Alan N.; Roederer, Mario; Bloch, Evan M.; Tobian, Aaron A.; Zyskind, Israel; Silverberg, Jonathan I.; Rosenberg, Avi Z.; Cox, Andrea L.; Lloyd, Tom; Mammen, Andrew L.; and Benjamin Larman, H, "Unbiased discovery of autoantibodies associated with severe COVID-19 via genome-scale self-assembled DNA-barcoded protein libraries" (2022). GW Authored Works. Paper 1561.