Project description:Post-acute sequelae of COVID-19 (PASC) represent an emerging global crisis. However, quantifiable risk-factors for PASC and their biological associations are poorly resolved. We executed a deep multi-omic, longitudinal investigation of 309 COVID-19 patients from initial diagnosis to convalescence (2-3 months later), integrated with clinical data, and patient-reported symptoms. We resolved four PASC-anticipating risk factors at the time of initial COVID-19 diagnosis: type 2 diabetes, SARS-CoV-2 RNAemia, Epstein-Barr virus viremia, and specific autoantibodies. In patients with gastrointestinal PASC, SARS-CoV-2-specific and CMV-specific CD8+ T cells exhibited unique dynamics during recovery from COVID-19. Analysis of symptom-associated immunological signatures revealed coordinated immunity polarization into four endotypes exhibiting divergent acute severity and PASC. We find that immunological associations between PASC factors diminish over time leading to distinct convalescent immune states. Detectability of most PASC factors at COVID-19 diagnosis emphasizes the importance of early disease measurements for understanding emergent chronic conditions and suggests PASC treatment strategies.
Project description:Although a substantial proportion of severe COVID-19 pneumonia survivors exhibit long-term pulmonary sequalae, the underlying mechanisms or associated local and systemic immune correlates are not known. Here, we have performed high dimensional characterization of the pathophysiological and immune traits of aged COVID-19 convalescents, and correlated the local and systemic immune profiles with pulmonary function and lung imaging. In this cohort of aged COVID-19 convalescents, chronic lung impairment was accompanied by persistent systemic inflammation and respiratory immune alterations. Detailed evaluation of the lung immune compartment revealed dysregulated respiratory CD8+ T cell responses that likely underlie the impaired lung function following acute COVID-19 during aging. Single cell transcriptomic analysis identified the potential pathogenic subsets of respiratory CD8+ T cells causing persistent tissue conditions following COVID-19. Our results have revealed key pathophysiological and immune traits that support the development of lung sequelae following SARS-CoV2 pneumonia during aging, with implications for the treatment of chronic COVID-19 symptoms.
Project description:Acute SARS-CoV-2 infection is often highly inflammatory and protracted. Recent advances have established that inflammation can trigger innate immune memory and a persistent influence on hematopoietic development, through epigenetic mechanisms. However, these phenotypes and their molecular and cellular features are poorly described in humans. Here we reveal epigenomic alterations in innate immune and hematopoietic stem and progenitor cells (HSPC) post-COVID-19, with distinct molecular programs across disease severities. Enabled by novel approaches to study hematopoiesis from peripheral blood, we find persisting HSPC epigenetic programs conveyed, for months to a year, to short-lived progeny monocytes. These epigenetic changes are associated with increased myeloid cell differentiation and inflammatory and antiviral programs. We provide insights into post-infectious HSPC and innate immune cell epigenetic alterations that are broadly relevant.
Project description:We performed longitudinal plasma proteomics analysis and determined absolute protein levels in a Canadian cohort (n=74) at admission day to hospital for acute COVID-19 and at 3 and 6 months after diagnosis of acute COVID-19. We measured plasma protein on a triple quadrupole mass spectrometer operated in multiple reaction monitoring mode and used internal standards to deduce protein absolute concentrations. We used a validated panel of 269 surrogate heavy labeled peptides. We also measured % predicted forced vital capacity (FVC, %) and diffusing capacity of the lungs for carbon monoxide (DLCO, %) by routine pulmonary function testing. We did functional enrichment and pathway analyses and determined proteins that were increased or decreased from hospital admission to 3-months and 6-months, compared females to males and determined associations of proteins with FVC% and DLCO%.
Project description:Genome-wide DNA methylation analysis of COVID-19 severity using the Illumina HumanMethylationEPIC microarray platform to analyze over 850,000 methylation sites, comparing COVID-19 patients during and one year after infection, using whole blood tissue.
Project description:Acute SARS-CoV-2 infection is often highly inflammatory and protracted. Recent advances have established that inflammation can trigger innate immune memory and a persistent influence on hematopoietic development, through epigenetic mechanisms. However, these phenotypes and their molecular and cellular features are poorly described in humans. Here we reveal epigenomic alterations in innate immune and hematopoietic stem and progenitor cells (HSPC) post-COVID-19, with distinct molecular programs across disease severities. Enabled by novel approaches to study hematopoiesis from peripheral blood, we find persisting HSPC epigenetic programs conveyed, for months to a year, to short-lived progeny monocytes. These epigenetic changes are associated with increased myeloid cell differentiation and inflammatory and antiviral programs. We provide insights into post-infectious HSPC and innate immune cell epigenetic alterations that are broadly relevant.