Molecular states during acute COVID-19 reveal distinct etiologies of long-term sequelae

Post-acute sequelae of SARS-CoV-2 infection are debilitating, clinically heterogeneous, and of unknown molecular etiology. A transcriptome-wide investigation was performed in acutely infected patients followed clinically into the post-acute period. Distinct gene-expression signatures of post-acute sequelae were already present in whole-blood during acute infection, with innate and adaptive immune cells implicated in different symptoms. Two clusters of sequelae exhibited divergent plasma-cell associated gene-expression patterns. In one cluster, sequelae associated with higher expression of immunoglobulin-related genes in an anti-spike antibody titer-dependent manner. In the other, sequelae associated independently of these titers with lower expression of immunoglobulin-related genes, indicating lower non-specific antibody production in subjects with these sequelae. This relationship between lower total immunoglobulins and sequelae was validated in an external cohort. Altogether, multiple etiologies of post-acute sequelae were already detectable during SARS-CoV-2 infection, directly linking these sequelae with the acute host response to the virus and providing early insights into their development. Bulk RNA-seq of whole blood sampled longitudinally from hospitalized COVID-19 cases during acute infection as well as from healthy and hospitalized controls. See https://www.synapse.org/#!Synapse:syn35874390/ for full clinical data, RNA-seq QC data, and other data and metadata. -------------------------- The Mount Sinai COVID-19 Biobank Team