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:The ongoing SARS-CoV-2 pandemic has resulted in over 6.3 million deaths and 560 million COVID-19 cases worldwide. Clinical management of hospitalised patients is complex due to the heterogeneous course of COVID-19. Low-dose radiotherapy (LD-RT) is known to dampen localised chronic inflammation, and has been suggested to be used to reduce lung inflammation in COVID-19 patients. However, it is unknown whether SARS-CoV-2 alters the radiation response and associated radiation exposure related risk. We generated gene expression profiles from circulating leukocytes of hospitalised COVID-19 patients and healthy donors. The p53 signalling pathway was found to be dysregulated, with mRNA levels of p53, ATM and CHK2 being lower in COVID-19 patients. Several key p53 target genes involved in cell cycle arrest, apoptosis and p53 feedback inhibition were up-regulated in COVID-19 patients, while other p53 target genes were downregulated. This dysregulation has functional consequences as the transcription of p53-dependant genes (CCNG1, GADD45A, DDB2, SESN1, FDXR, APOBEC) was reduced 24 h after X-ray exposure ex-vivo to both low (100 mGy) or high (2 Gy) doses. In conclusion, SARS-CoV-2 infection affects a DNA damage response that may modify radiation-induced health risks in exposed COVID-19 patients.
Project description:Red blood cells (RBC) depleted whole blood from COVID-19 patients and controls was harvested and processed in order to performed 10X single cell RNA-seq. For COVID-19 patients 2 samples 10 days a part were analyzed.
Project description:In this prospective observational cohort study, we found transcriptional evidence that persistent immune dysfunction was associated with 28-day mortality in both COVID-19 and non-COVID-19 septic patients. COVID-19 patients had an early antiviral response but became indistinguishable on a gene expression level from non-COVID-19 sepsis patients a week later. Early treatment of COVID-19 and non-COVID-19 sepsis ICU patients should focus on pathogen control, but both patient groups also require novel immunomodulatory treatments, particularly later during ICU hospitalization, independent of admission diagnosis. Some T1 samples were uploaded in GSE185263 and were not re-uploaded in this series.
Project description:The causative organism, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), exhibits a wide spectrum of clinical manifestations in disease-ridden patients. Differences in the severity of COVID-19 ranges from asymptomatic infections and mild cases to the severe form, leading to acute respiratory distress syndrome (ARDS) and multiorgan failure with poor survival. MiRNAs can regulate various cellular processes, including proliferation, apoptosis, and differentiation, by binding to the 3′UTR of target mRNAs inducing their degradation, thus serving a fundamental role in post-transcriptional repression. Alterations of miRNA levels in the blood have been described in multiple inflammatory and infectious diseases, including SARS-related coronaviruses. We used microarrays to delineate the miRNAs and snoRNAs signature in the peripheral blood of severe COVID-19 cases (n=9), as compared to mild (n=10) and asymptomatic (n=10) patients, and identified differentially expressed transcripts in severe versus asymptomatic, and others in severe versus mild COVID-19 cases. A cohort of 29 male age-matched patients were selected. All patients were previously diagnosed with COVID-19 using TaqPath COVID-19 Combo Kit (Thermo Fisher Scientific, Waltham, Massachusetts), or Cobas SARS-CoV-2 Test (Roche Diagnostics, Rotkreuz, Switzerland), with a CT value < 30. Additional criterion for selection was age between 35 and 75 years. Participants were grouped into severe, mild and asymptomatic. Classifying severe cases was based on requirement of high-flow oxygen support and ICU admission (n=9). Whereas mild patients were identified based on symptoms and positive radiographic findings with pulmonary involvement (n=10). Patients with no clinical presentation were labelled as asymptomatic cases (n=10).
Project description:Although most SARS-CoV-2-infected individuals experience mild COVID-19, some patients suffer from severe COVID-19, which is accompanied by acute respiratory distress syndrome and systemic inflammation. To identify factors driving severe progression of COVID-19, we performed single-cell RNA-seq using peripheral blood mononuclear cells (PBMCs) obtained from healthy donors, patients with mild or severe COVID-19, and patients with severe influenza. Patients with COVID-19 exhibited hyper-inflammatory signatures across all types of cells among PBMCs, particularly upregulation of the TNF/IL-1beta-driven inflammatory response as compared to severe influenza. In classical monocytes from patients with severe COVID-19, type I IFN response co-existed with the TNF/IL-1beta-driven inflammation, and this was not seen in patients with milder COVID-19 infection. Based on this, we propose that the type I IFN response exacerbates inflammation in patients with severe COVID-19 infection.
Project description:Although some studies reported the comprehensive mRNA expression analysis of coronavirus disease 2019 (COVID-19) using blood samples to understand its pathogenesis, the characteristics of RNA expression in COVID-19 and sepsis have not been compared. We compared the transcriptome expression of whole blood samples from patients with COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and patients with sepsis caused by other bacteria who entered the intensive care unit to clarify the COVID-19-specific RNA expression and understand its pathogenesis. Transcriptomes related to mitochondria were upregulated in COVID-19, whereas those related to neutrophils were upregulated in sepsis. However, the transcriptomes related to neutrophils were upregulated in both COVID-19 and sepsis compared to in healthy controls, whereas the mitochondrial transcriptomes were upregulated in COVID-19 and downregulated in sepsis compared to in healthy controls. Moreover, sepsis showed sub-optimal intrinsic apoptotic features compared with COVID-19. The transcriptome expression of COVID-19 has been examined in vitro but has not been widely validated using human specimens. This study improves the understanding of the pathogenesis of COVID-19 and can contribute to the development of treatments.