Dataset Information

Multi-Omics Integration Reveals Only Minor Long-Term Molecular and Functional Sequelae in Immune Cells of Individuals Recovered From COVID-19.

ABSTRACT: The majority of COVID-19 patients experience mild to moderate disease course and recover within a few weeks. An increasing number of studies characterized the long-term changes in the specific anti-SARS-CoV-2 immune responses, but how COVID-19 shapes the innate and heterologous adaptive immune system after recovery is less well known. To comprehensively investigate the post-SARS-CoV-2 infection sequelae on the immune system, we performed a multi-omics study by integrating single-cell RNA-sequencing, single-cell ATAC-sequencing, genome-wide DNA methylation profiling, and functional validation experiments in 14 convalescent COVID-19 and 15 healthy individuals. We showed that immune responses generally recover without major sequelae after COVID-19. However, subtle differences persist at the transcriptomic level in monocytes, with downregulation of the interferon pathway, while DNA methylation also displays minor changes in convalescent COVID-19 individuals. However, these differences did not affect the cytokine production capacity of PBMCs upon different bacterial, viral, and fungal stimuli, although baseline release of IL-1Ra and IFN-γ was higher in convalescent individuals. In conclusion, we propose that despite minor differences in epigenetic and transcriptional programs, the immune system of convalescent COVID-19 patients largely recovers to the homeostatic level of healthy individuals.

SUBMITTER: Liu Z

PROVIDER: S-EPMC9022455 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Multi-Omics Integration Reveals Only Minor Long-Term Molecular and Functional Sequelae in Immune Cells of Individuals Recovered From COVID-19.

Liu Zhaoli Z Kilic Gizem G Li Wenchao W Bulut Ozlem O Gupta Manoj Kumar MK Zhang Bowen B Qi Cancan C Peng He H Tsay Hsin-Chieh HC Soon Chai Fen CF Mekonnen Yonatan Ayalew YA Ferreira Anaísa Valido AV van der Made Caspar I CI van Cranenbroek Bram B Koenen Hans J P M HJPM Simonetti Elles E Diavatopoulos Dimitri D de Jonge Marien I MI Müller Lisa L Schaal Heiner H Ostermann Philipp N PN Cornberg Markus M Eiz-Vesper Britta B van de Veerdonk Frank F van Crevel Reinout R Joosten Leo A B LAB Domínguez-Andrés Jorge J Xu Cheng-Jian CJ Netea Mihai G MG Li Yang Y

Frontiers in immunology 20220406

The majority of COVID-19 patients experience mild to moderate disease course and recover within a few weeks. An increasing number of studies characterized the long-term changes in the specific anti-SARS-CoV-2 immune responses, but how COVID-19 shapes the innate and heterologous adaptive immune system after recovery is less well known. To comprehensively investigate the post-SARS-CoV-2 infection sequelae on the immune system, we performed a multi-omics study by integrating single-cell RNA-sequenc ...[more]

PMID: 35464396

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Project description:BackgroundApproximately 10-30% of individuals continue to experience symptoms classified as post-acute sequelae of coronavirus disease 2019 (COVID-19 (PASC)). PASC is a multisystem condition primarily characterized by respiratory symptoms, such as reduced diffusing capacity for carbon monoxide (DLco). Although many studies have investigated the pathogenesis of acute COVID-19, the long-term molecular changes in COVID-19 convalescents with PASC remain poorly understood.MethodsWe prospectively recruited 70 individuals who had been diagnosed with COVID-19 from 7 January 2020 to 29 May 2020 (i.e., COVID-19 convalescents); we performed follow-up visits at 6 months, 1 year, 2 years, and 3 years after hospital discharge. Thirty-five healthy controls (CONs), recruited from a physical examination center before the COVID-19 pandemic, served as a comparison group. We explored the proteomic and metabolomic profiles of 174 plasma samples from the 70 COVID-19 convalescents and 35 CONs.ResultsWe performed a comprehensive molecular analysis of COVID-19 convalescents to investigate host changes up to 3 years after hospital discharge. Our multi-omics analysis revealed activation of cytoskeletal organization and glycolysis/gluconeogenesis, as well as suppression of gas transport and adaptive immune responses, in COVID-19 convalescents. Additionally, metabolites involved in glutathione metabolism; alanine, aspartate, and glutamate metabolism; and ascorbate and aldarate metabolism were significantly upregulated in COVID-19 convalescents. Pulmonary and molecular abnormalities persisted for 3 years in COVID-19 convalescents; impaired diffusing capacity for carbon monoxide (DLco) was the most prominent feature. We used this multi-omics profile to develop a model involving one protein (heterogeneous nuclear ribonucleoprotein K (HNRNPK)) and two metabolites (arachidonoyl-EA and 1-O-(2r-hydroxy-pentadecyl)-sn-glycerol)) for identification of COVID-19 convalescents with abnormal DLco.ConclusionsThese data provide insights concerning molecular sequelae among COVID-19 convalescents up to 3 years after hospital discharge, clarify mechanisms driving respiratory sequelae, and support the development of a novel model to predict reduced DLco. This longitudinal multi-omics analysis may illuminate the trajectory of altered lung function in COVID-19 convalescents.

Project description:BackgroundThe plasticity of monocytes enables them to exert multiple roles during an immune response, including promoting immune tolerance. How monocytes alter their functions to convey immune tolerance in the context of lower respiratory tract infections in humans is not well understood. Here, we sought to identify epigenetic and transcriptomic features of cytokine production capacity in circulating monocytes during community-acquired pneumonia (CAP).MethodsCirculating CD14+ monocytes were obtained from the blood of CAP patients included in a longitudinal, observational cohort study, on hospitalization (acute stage, n=75), and from the same patients after a 1-month follow-up (recovery stage, n=56). Age and sex-matched non-infectious participants were included as controls (n=41). Ex vivo cytokine production after lipopolysaccharide (LPS) exposure was assessed by multiplex assay. Transcriptomes of circulating monocytes were generated by RNA-sequencing, and DNA methylation levels in the same monocytes were measured by reduced representation bisulfite sequencing. Data were integrated by fitting projection-to-latent-structure models, and signatures derived by partial least squares discrimination.ResultsMonocytes captured during the acute stage exhibited impaired TNF, IL-1β, IL-6, and IL-10 production after ex vivo stimulation with LPS, relative to controls. IL-6 production was not resolved in recovery monocytes. Multivariate analysis of RNA-sequencing data identified 2938 significantly altered RNA transcripts in acute-stage monocytes (fold expression ≤-1.5 or ≥1.5; adjusted p ≤ 0.01), relative to controls. Comparing DNA methylation levels in circulating monocytes of CAP patients to controls revealed minimal differences, specifically in DNAse hypersensitive sites (HS) of acute-stage monocytes. Data integration identified a cholesterol biosynthesis gene signature and DNAse HS axis of IL-1β and IL-10 production (R2 =0.51).ConclusionsCirculating monocytes obtained from CAP patients during the acute stage exhibited impaired cytokine production capacities, indicative of reprogramming to a state of immune tolerance, which was not fully resolved after 1 month. Our split-sample study showed that 51% of the immune tolerance phenotype can be explained, at least in part, by coordinated shifts in cholesterol biosynthesis gene expression and DNAse HS methylation levels. A multi-scale model identified an epigenetic and transcriptomic signature of immune tolerance in monocytes, with implications for future interventions in immunosuppression.Trial registrationNCT number NCT02928367.

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Multi-Omics Integration Reveals Only Minor Long-Term Molecular and Functional Sequelae in Immune Cells of Individuals Recovered From COVID-19.

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Multi-Omics Integration Reveals Only Minor Long-Term Molecular and Functional Sequelae in Immune Cells of Individuals Recovered From COVID-19.

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