Persistent serum protein signatures define an inflammatory subset of long COVID

Readme: This repository consists of the data and R-code to generate the figures of the manuscript. .R Code chunks with the prefix 1-5 contains code for the Rule-in and module based approach to identify PASC clusters, corresponding to Figure 1A and Supplementary figure 3B. .R Code chunk with the prefix 6 contains code of the deeper dive Olink analysis, antibody titer analysis and clinical activity score analysis post identifying PASC clusters, corresponding to all other figures of the manuscript. One Sentence Summary: Serum proteome profiling identifies subsets of long COVID patients with evidence of persistent inflammation including key immune signaling pathways that may be amenable to therapeutic intervention. Abstract: Long COVID or post-acute sequelae of SARS-CoV-2 (PASC) is a clinical syndrome featuring diverse symptoms that can persist for months after acute SARS-CoV-2 infection. The etiologies are unknown but may include persistent inflammation, unresolved tissue damage, or delayed clearance of viral protein or RNA. Attempts to classify subsets of PASC by symptoms alone have been unsuccessful. To molecularly define PASC, we evaluated the serum proteome in longitudinal samples from 55 PASC individuals with symptoms lasting ≥60 days after onset of acute infection and compared this to symptomatically recovered SARS-CoV-2 infected and uninfected individuals. We identified subsets of PASC with distinct signatures of persistent inflammation. Type II interferon signaling and canonical NF-κB signaling (particularly associated with TNF), were the most differentially enriched pathways. These findings help to resolve the heterogeneity of PASC, identify patients with molecular evidence of persistent inflammation, and highlight dominant pathways that may have diagnostic or therapeutic relevance.