Unbiased discovery of autoantibodies associated with severe COVID-19 via genome-scale self-assembled DNA-barcoded protein libraries

MIPSA covalently couples each ORF-encoded protein to a unique DNA barcode (a unique-clone-identifier, or UCI) inside its translation complex via a HaloTag fusion, so an entire ORFeome can be displayed and immunoprecipitated in a single pooled reaction and read out by sequencing. Compared with phage display (which is restricted to short peptides) and protein microarrays (which are expensive and dry-spotting-prone), MIPSA delivers full-length, conformational, soluble proteins at proteome scale.

Of the four severe-COVID-19 patients carrying neutralizing IFN-α autoantibodies, two died — a fatality rate substantially higher than the rest of the severe cohort. MIPSA also detected NT5C1A autoantibodies (the canonical inclusion-body-myositis target) in 3 of 55 severe patients, confirming the assay surfaces clinically meaningful autoreactivities beyond the interferon axis.

By covalently coupling each ORF-encoded full-length protein to its own DNA barcode through self-assembly inside the translation complex, MIPSA pushes proteome-scale antibody profiling past the peptide-fragment ceiling that has long constrained phage display — with a sequencing readout that costs and scales like PhIP-Seq, not like a protein microarray. The COVID-19 cohort is its first published clinical demonstration; the platform itself is the technology Infinity Bio operates as the HuSIGHT human-proteome reactome service. For autoantibody-discovery groups working in complex disease, MIPSA captures conformational autoepitopes that peptide phage display systematically misses, and the dataset is directly reusable for long-COVID and post-acute sequelae studies.