Molecular states during acute COVID-19 reveal distinct etiologies of long-term sequelae.
Link: https://doi.org/10.1038/s41591-022-02107-4
Authors: Thompson, Ryan C; Simons, Nicole W; Wilkins, Lillian; Cheng, Esther; Del Valle, Diane Marie; Hoffman, Gabriel E; Cervia, Carlo; Fennessy, Brian; Mouskas, Konstantinos; Francoeur, Nancy J; Johnson, Jessica S; Lepow, Lauren; Le Berichel, Jessica; Chang, Christie; Beckmann, Aviva G; Wang, Ying-Chih; Nie, Kai; Zaki, Nicholas; Tuballes, Kevin; Barcessat, Vanessa; Cedillo, Mario A; Yuan, Dan; Huckins, Laura; Roussos, Panos; Marron, Thomas U; , ; Glicksberg, Benjamin S; Nadkarni, Girish; Heath, James R; Gonzalez-Kozlova, Edgar; Boyman, Onur; Kim-Schulze, Seunghee; Sebra, Robert; Merad, Miriam; Gnjatic, Sacha; Schadt, Eric E; Charney, Alexander W; Beckmann, Noam D
Abstract: Post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are debilitating, clinically heterogeneous and of unknown molecular etiology. A transcriptome-wide investigation was performed in 165 acutely infected hospitalized individuals who were 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 individuals 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.