Project description:Aging is classically conceptualized as an ever-increasing trajectory of damage accumulation and loss of function, leading to increases in morbidity and mortality. However, recent in vitro studies have raised the possibility of age reversal. We characterized several models in which biological age, assessed primarily through analysis of DNA methylation, undergoes reversible changes. Severe COVID-19 is one such example.
Project description:In managing patients with coronavirus disease 2019 (COVID-19), early identification of those at high risk and real-time monitoring of disease progression to severe COVID-19 is a major challenge. We aimed to identify early prognostic protein markers and to discover surrogate protein markers that effectively reflect the clinical progression of the disease. We performed in-depth proteome profiling on 137 sera, longitudinally collected from 25 patients with COVID-19 (non-severe patients, n = 13; patients who progressed to severe COVID-19, n = 12). We identified 11 potential biomarkers, including the novel markers IGLV3-19 and BNC2, as early prognostic indicators of severe COVID-19. These potential biomarkers are mainly involved in biological processes associated with humoral immune response, interferon signalling, acute phase response, lipid metabolism, and platelet degranulation. We further revealed that the longitudinal changes of 40 proteins persistently increased or decreased as the disease progressed to severe COVID-19. These 40 potential biomarkers could effectively reflect the clinical progression of the disease. This study supports the development of protein biomarkers, which might enable better predicting and monitoring progression to severe COVID-19.
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:The acute respiratory distress syndrome (ARDS) is a common complications of severe COVID-19 and contributes to patient morbidity and mortality. ARDS is a heterogeneous syndrome caused by various insults, and results in acute hypoxemic respiratory failure. Patients with ARDS from COVID-19 may represent a subgroup of ARDS patients with distinct molecular profiles that drive disease outcomes. Here, we hypothesized that longitudinal transcriptomic analysis may identify distinct dynamic pathobiological pathways during COVID-19 ARDS. We identified a patient cohort from an existing ICU biorepository and established three groups for comparison: 1) patients with COVID-19 ARDS that survived hospitalization (COVID survivors, n = 4), 2) patients with COVID-19 ARDS that did not survive hospitalization (COVID non-survivors, n = 5), and 3) patients with ARDS from other causes as a control group (ARDS controls, n = 4). RNA was extracted from peripheral blood mononuclear cells (PBMCs) at 4 time points (Days 1, 3, 7, and 10 following ICU admission) and prepared for RNA sequencing with rRNA depletion and library generation for Illumina. An Illumina NovaSeq X Plus instrument was used to generate 150 base pair paired-end reads, which were aligned to the hg GRCh38.96 reference genome using HiSAT2. Differential expression analysis was performed with DESeq2.
Project description:We profiled the single-cell transcriptomes of 13,289 peripheral blood mononuclear cells isolated at three longitudinal stages from two severe COVID-19 patients treated with Tocilizumab. The raw sequencing data can be obtained from the Genome Sequence Archive for Human (GSA-Human) at https://bigd.big.ac.cn/gsa-human/browse/HRA000172 .
Project description:COVID-19 induces profound B-cell dysregulation, notably a marked expansion of plasmablasts (PB), whose functional role remains unclear. This study aimed to characterize PB dynamics and functions in COVID-19 and their association with disease severity. We performed longitudinal immune profiling in a prospective cohort of 50 patients with COVID-19 (cohort 1), including flow cytometry-based B-cell immunophenotyping and multiplex cytokine analysis at days 1, 7, 14, and 30. A second retrospective cohort of 282 corticosteroid-naïve patients (cohort 2) was used to validate PB dynamics, model PB trajectories, and perform transcriptomic profiling of sorted PB. PB expansion occurred early in COVID-19 and was positively correlated with maximal disease severity (r=0.53, p<0.0001). Two distinct PB expansion trajectories were identified: one rapidly resolving, and one persistent and amplified, the latter being associated with higher severity scores and 30-day mortality (31% vs. 5%, p<0.001). In cohort 1, BAFF levels at day 7 correlated positively with both PB proportion (r=0.59, p=0.002) and maximal disease severity (r=0.74, p<0.001). Transcriptomic profiling of PB in cohort 2 revealed severity-specific signatures: in severe cases, early PB upregulated genes related to purine metabolism and CD39 expression, suggesting a pro-inflammatory role. In non-severe cases, PB expressed interferon-related and CIITA-mediated MHC-II programs, indicative of antiviral function. PB display dual functional profiles in COVID-19, acting either as regulators of antiviral immunity or as amplifiers of inflammation in severe disease. These findings support exploring therapeutic strategies targeting the BAFF-PB axis in severe COVID-19.
Project description:SARS-CoV-2, a highly contagious and infectious virus is responsible for causing this COVID-19 pandemic, which has a substantial impact on global health and economy. The spectrum of clinical manifestations of COVID-19 ranges from mild or non-severe state to severe life-threatening condition in some group of people. Many patients are likely to undergo non-severe to severe transition during their infection period. For this study, we have collected blood samples of different time points from patients showing both non-severe to severe and severe to recovered transition. The clinical information of the patient’s condition is obtained from their medical records. We have investigated the proteome of different time points of the patient’s sample to analyse their trend in prognosis of the disease.
Project description:Manuscript describes the daily dynamics of transcriptional responses in whole blood, from acute to convalescent phase, in severe and non-severe COVID-19 patients.
Project description:Mechanisms of neutrophil involvement in severe COVID-19 remain incompletely understood. Here we collect longitudinal blood samples from 306 hospitalized COVID-19+ patients and 86 controls, and perform bulk RNA-sequencing of enriched neutrophils, plasma proteomics, and high-throughput antibody profiling to investigate relationships between neutrophil states and disease severity. We identify dynamic switches between 6 distinct neutrophil subtypes. At days 3 and 7 post-hospitalization, patients with severe disease display a granulocytic myeloid-derived suppressor cell-like gene expression signature, while patients with resolving disease show a neutrophil progenitor-like signature. Humoral responses are identified as potential drivers of neutrophil effector functions, with elevated SARS-CoV-2-specific IgG1-to-IgA1 ratios in plasma of severe patients who survived. In vitro experiments confirm that while patient-derived IgG antibodies induce phagocytosis in healthy donor neutrophils, IgA antibodies predominantly induce neutrophil cell death. Overall, our study demonstrates a dysregulated myelopoietic response in severe COVID-19 and a potential role for IgA-dominant responses contributing to mortality.