Journal Article

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

Lepow, Lauren, Beckmann, Aviva G., Barcessat, Vanessa, Sebra, Robert, Nie, Kai, Marron, Thomas U., Chang, Christie, Gonzalez-Kozlova, Edgar, Mouskas, Konstantinos, Cheng, Esther, Schadt, Eric E., Fennessy, Brian, Yuan, Dan, Johnson, Jessica S., Thompson, Ryan C., Glicksberg, Benjamin S., Le Berichel, Jessica, Hoffman, Gabriel E., Cervia, Carlo, Huckins, Laura, Charney, Alexander W., Zaki, Nicholas, Nadkarni, Girish, Roussos, Panos, Wang, Ying-chih, Heath, James R., Kim-Schulze, Seunghee, Tuballes, Kevin, Wilkins, Lillian, Boyman, Onur, Merad, Miriam, Gnjatic, Sacha, Beckmann, Noam D., Simons, Nicole W., Del Valle, Diane Marie, Cedillo, Mario A., Francoeur, Nancy J.

2023

Overview

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. Transcriptomic analyses of acute phase whole blood from a large cohort of patients with COVID-19 identify molecular determinants of post-infection long-term sequelae.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/114/2403 / 631/250/2502 / 631/250/255 / 631/337/2019 / 692/699/255/2514 / Antibodies / Antibodies, Viral / Biomedical and Life Sciences / Biomedicine / Blood / Cancer Research / Complications / Coronaviruses / COVID-19 / COVID-19 - genetics / Divergence / Etiology / Gene expression / Genes / Humans / Immune response / Immune system / Immunoglobulins / Infections / Infectious Diseases / Metabolic Diseases / Molecular Medicine / Neurosciences / Respiratory diseases / SARS-CoV-2 / Severe acute respiratory syndrome coronavirus 2 / Transcriptomes / Transcriptomics / Viral diseases