SARS-CoV-2 infection induces a long-lived pro-inflammatory transcriptional profile

• Published in: Genome medicine Vol. 15; no. 1; pp. 1 - 12
• Main Authors: Zhang, Jia-Yuan, Whalley, Justin P, Knight, Julian C, Wicker, Linda S, Todd, John A, Ferreira, Ricardo C
• Format: Journal Article
• Language: English
• Published: London BioMed Central Ltd 12.09.2023; BioMed Central; BMC
• Subjects: Analysis; Autoimmune diseases; Beta cells; Care and treatment; Coronaviruses; COVID-19; Cytokines; Datasets; Diabetes mellitus (insulin dependent); Gene expression; Gene regulation; Genes; Genetic aspects; Genetic research; Genetic transcription; Health aspects; IL-2-induced anti-inflammatory signature; Immune response; Immunotherapy; Independent variables; Infections; Inflammation; Interleukin 2; Killer cells; Long-term effects; Lymphocytes; Medical research; Medicine, Experimental; Microbiomes; Monocytes; NF-kB; NF-κB protein; Patients; Post-acute sequelae of COVID-19 (PASC); SARS-CoV-2; Sepsis; Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Single-cell multiomics; Transcriptomics; Tumor necrosis factor-TNF; Type 1 diabetes; Viral infections
• ISSN: 1756-994X; 1756-994X
• DOI: 10.1186/s13073-023-01227-x

Background The immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in COVID-19 patients has been extensively investigated. However, much less is known about the long-term effects of infection in patients and how it could affect the immune system and its capacity to respond to future perturbations. Methods Using a targeted single-cell multiomics approach, we have recently identified a prolonged anti-inflammatory gene expression signature in T and NK cells in type 1 diabetes patients treated with low-dose IL-2. Here, we investigated the dynamics of this signature in three independent cohorts of COVID-19 patients: (i) the Oxford COVID-19 Multi-omics Blood Atlas (COMBAT) dataset, a cross-sectional cohort including 77 COVID-19 patients and ten healthy donors; (ii) the INCOV dataset, consisting of 525 samples taken from 209 COVID-19 patients during and after infection; and (iii) a longitudinal dataset consisting of 269 whole-blood samples taken from 139 COVID-19 patients followed for a period of up to 7 months after the onset of symptoms using a bulk transcriptomic approach. Results We discovered that SARS-CoV-2 infection leads to a prolonged alteration of the gene expression profile of circulating T, B and NK cells and monocytes. Some of the genes affected were the same as those present in the IL-2-induced anti-inflammatory gene expression signature but were regulated in the opposite direction, implying a pro-inflammatory status. The altered transcriptional profile was detected in COVID-19 patients for at least 2 months after the onset of the disease symptoms but was not observed in response to influenza infection or sepsis. Gene network analysis suggested a central role for the transcriptional factor NF-κB in the regulation of the observed transcriptional alterations. Conclusions SARS-CoV-2 infection causes a prolonged increase in the pro-inflammatory transcriptional status that could predispose post-acute patients to the development of long-term health consequences, including autoimmune disease, reactivation of other viruses and disruption of the host immune system-microbiome ecosystem. Keywords: COVID-19, SARS-CoV-2, Post-acute sequelae of COVID-19 (PASC), IL-2-induced anti-inflammatory signature, NF-kB, Single-cell multiomics