ABSTRACT
Post-COVID syndrome (PCS) currently affects approximately 3-17% of people following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and has the potential to become a significant global health burden. PCS presents with various symptoms, and methods for improved PCS assessment are presently developed to guide therapy. Nevertheless, there are few mechanistic insights and treatment options. Here, we performed single-cell RNA transcriptomics on nasal biopsies from 33 patients suffering from PCS with mild, moderate, or severe symptoms. We identified 17 different cell clusters representing 12 unique cell populations, including all major epithelial cell types of the conducting airways and basal, secretory, and ciliated cells. Severe PCS was associated with decreased numbers of ciliated cells and the presence of immune cells. Ensuing inflammatory signaling upregulated TGF{beta} and induced an epithelial-mesenchymal transition, which led to the high abundance of basal cells and a mis-stratified epithelium. We confirmed the results in vitro using an air-liquid interface culture and validated TNF as the causal inflammatory cytokine. In summary, our results show that one mechanism for sustained PCS is not through continued viral load, but through the presence of immune cells in nasal tissue leading to impaired mucosal barrier function and repeated infections. These findings could be further explored as a therapeutic option akin to other chronic inflammatory diseases by inhibiting the TNF-TGF{beta} axis, restoring the nasal epithelium, and reducing respiratory tract-related infections.
Subject(s)
Coronavirus Infections , Post-Concussion SyndromeABSTRACT
Immune perturbation is a hallmark of Coronavirus Disease 2019 (COVID-19) with ambiguous roles of various immune cell compartments. Plasma cells, responsible for antibody production, have a two-pronged response while mounting an immune defence with 1) physiological immune response producing neutralizing antibodies against protein structures of SARS-CoV-2 and 2) potentially deleterious autoantibody generation. Growing evidence hints towards broad activation of plasma cells and the presence of pathologic autoantibodies (abs) that mediate immune perturbation in acute COVID-19 [1]. Recently, a systematic screening for abs confirmed induction of diverse functional abs in SARS-CoV-2 infection, targeting several immunomodulatory proteins, including cytokines/chemokines and their respective G-protein coupled receptors (GPCR) [1]. Abs against GPCR act as agonistic and allosteric receptor modulators and are linked to chronic inflammatory diseases [2] and, as we recently demonstrated, disease severity in acute COVID-19 [3].
ABSTRACT
Due to the highly variable clinical phenotype of Coronavirus disease 2019 (COVID-19), deepening the host genetic contribution to severe COVID-19 may further improve our understanding about underlying disease mechanisms. Here, we describe an extended GWAS meta-analysis of 3,260 COVID-19 patients with respiratory failure and 12,483 population controls from Italy, Spain, Norway and Germany, as well as hypothesis-driven targeted analysis of the human leukocyte antigen (HLA) region and chromosome Y haplotypes. We include detailed stratified analyses based on age, sex and disease severity. In addition to already established risk loci, our data identify and replicate two genome-wide significant loci at 17q21.31 and 19q13.33 associated with severe COVID-19 with respiratory failure. These associations implicate a highly pleiotropic ~0.9-Mb 17q21.31 inversion polymorphism, which affects lung function and immune and blood cell counts, and the NAPSA gene, involved in lung surfactant protein production, in COVID-19 pathogenesis.
Subject(s)
COVID-19 , Respiratory InsufficiencyABSTRACT
The pandemic spread of the potentially life-threatening disease COVID-19 requires a thorough understanding of the longitudinal dynamics of host responses. Temporal resolution of cellular features associated with a severe disease trajectory will be a pre-requisite for finding disease outcome predictors. Here, we performed a longitudinal multi-omics study using a two-centre German cohort of 13 patients (from Cologne and Kiel, cohort 1). We analysed the bulk transcriptome, bulk DNA methylome, and single-cell transcriptome (>358,000 cells, including BCR profiles) of peripheral blood samples harvested from up to 5 time points. The results from single-cell and bulk transcriptome analyses were validated in two independent cohorts of COVID-19 patients from Bonn (18 patients, cohort 2) and Nijmegen (40 patients, cohort 3), respectively. We observed an increase of proliferating, activated plasmablasts in severe COVID-19, and show a distinct expression pattern related to a hyperactive cellular metabolism of these cells. We further identified a notable expansion of type I IFN-activated circulating megakaryocytes and their progenitors, indicative of emergency megakaryopoiesis, which was confirmed in cohort 2. These changes were accompanied by increased erythropoiesis in the critical phase of the disease with features of hypoxic signalling. Finally, projecting megakaryocyte- and erythroid cell-derived co-expression modules to longitudinal blood transcriptome samples from cohort 3 confirmed an association of early temporal changes of these features with fatal COVID-19 disease outcome. In sum, our longitudinal multi-omics study demonstrates distinct cellular and gene expression dynamics upon SARS-CoV-2 infection, which point to metabolic shifts of circulating immune cells, and reveals changes in megakaryocytes and increased erythropoiesis as important outcome indicators in severe COVID-19 patients.