What drives fatal cases of COVID-19 in vaccinees?
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB49094 | ENA |
REPOSITORIES: ENA
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Project description:Respiratory failure in COVID-19 is characterized by widespread disruption of the lung’s alveolar gas exchange interface. To elucidate determinants of alveolar lung damage, we performed epithelial and immune cell profiling in lungs from 24 COVID-19 autopsies and 43 uninfected organ donors ages 18-92 years. We found marked loss of type 2 alveolar epithelial (T2AE) cells and increased peri-alveolar lymphocyte cytotoxicity in all fatal COVID-19 cases, even at early stages before typical patterns of acute lung injury are histologically apparent. In lungs from uninfected organ donors, there is also progressive loss of T2AE with increasing age which may increase susceptibility to COVID-19 mediated lung damage in older individuals. In the fatal COVID-19 cases, macrophage infiltration differed according to the histopathological pattern of lung injury. In cases with acute lung injury, we found accumulation of CD4+ macrophages that express distinctly high levels of T-cell activation and co-stimulation genes and strongly correlate with increased extent of alveolar epithelial cell depletion and CD8 T-cell cytotoxicity. Together, our results show that T2AE deficiency may underlie age-related COVID-19 risk and initiate alveolar dysfunction shortly after infection; and we define immune cell mediators that may contribute to alveolar injury in distinct pathological stages of fatal COVID-19.
2022-04-19 | GSE200988 | GEO
Project description:Single-cell RNA-sequencing reveals a shift from focused IFN alpha-driven signals in COVID-19 ICU patients who survive to broad pro-inflammatory responses in fatal COVID-19 – a feature not observed in severe influenza. We conclude that fatal COVID-19 infection is driven by uncoordinated inflammatory responses that drive a hierarchy of T cell activation, elements of which can serve as prognostic indicators and potential targets for immune intervention.
2021-06-18 | GSE178404 | GEO
Project description:<p>SARS-CoV-2 infection causes severe pulmonary manifestations, with poorly understood mechanisms and limited treatment options. Hyperferritinemia and disrupted lung iron homeostasis in COVID-19 patients imply that ferroptosis, an iron-dependent cell death, may occur. Immunostaining and lipidomic analysis in COVID-19 lung autopsies reveal increases in ferroptosis markers, including transferrin receptor 1 and malondialdehyde accumulation in fatal cases. COVID-19 lungs display dysregulation of lipids involved in metabolism and ferroptosis. We find increased ferritin light chain associated with severe COVID-19 lung pathology. Iron overload promotes ferroptosis in both primary cells and cancerous lung epithelial cells. In addition, ferroptosis markers strongly correlate with lung injury severity in a COVID-19 lung disease model using male Syrian hamsters. These results reveal a role for ferroptosis in COVID-19 pulmonary disease; pharmacological ferroptosis inhibition may serve as an adjuvant therapy to prevent lung damage during SARS-CoV-2 infection.</p>
2024-07-11 | MTBLS3107 | MetaboLights
Project description:Our understanding of protective vs. pathologic immune responses to SARS-CoV-2, the virus that causes Coronavirus disease 2019 (COVID-19), is limited by inadequate profiling of patients at the extremes of the disease severity spectrum. Here, we performed multi-omic single-cell immune profiling of 64 COVID-19 patients across the full range of disease severity, from outpatients with mild disease to fatal cases. Our transcriptomic, epigenomic, and proteomic analyses reveal widespread dysfunction of peripheral innate immunity in severe and fatal COVID-19, with the most profound disturbances including prominent hyperactivation signatures in neutrophils and monocytes with anti-inflammatory features. We also leverage epigenomic analysis to identify loss of accessibility at NF-kB binding sites within pro-inflammatory cytokine gene loci as a potential mechanism for the striking lack of cytokine production observed in monocytes in severe and fatal COVID-19. We further demonstrate that emergency myelopoiesis is a prominent feature of fatal COVID-19. Collectively, our results reveal disease severity-associated immune phenotypes in COVID-19 and identify pathogenesis-associated pathways that are potential targets for therapeutic intervention.
2021-05-08 | GSE174072 | GEO
Project description:Information on the immunopathobiology of coronavirus disease 2019 (COVID-19) is rapidly increasing; however, there remains a need to identify immune features predictive of fatal outcome. This large-scale study characterized immune responses to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection using multidimensional flow cytometry, with the aim of identifying high-risk immune biomarkers. Holistic and unbiased analyses of 17 immune cell-types were conducted on 1,075 peripheral blood samples obtained from 868 COVID-19 patients and on samples from 24 patients presenting with non-SARS-CoV-2 infections and 36 healthy donors. Immune profiles of COVID-19 patients were significantly different from those of age-matched healthy donors but generally similar to those of patients with non-SARS-CoV-2 infections. Unsupervised clustering analysis revealed three immunotypes during SARS-CoV-2 infection; immunotype 1 (14% of patients) was characterized by significantly lower percentages of all immune cell-types except neutrophils and circulating plasma cells, and was significantly associated with severe disease. Reduced B-cell percentage was most strongly associated with risk of death. On multivariate analysis incorporating age and comorbidities, B-cell and non-classical monocyte percentages were independent prognostic factors for survival in training (n=513) and validation (n=355) cohorts. Therefore, reduced percentages of B-cells and non-classical monocytes are high-risk immune biomarkers for risk-stratification of COVID-19 patients.
2021-05-03 | GSE155897 | GEO
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).
2022-03-01 | E-MTAB-10970 | biostudies-arrayexpress
Project description:To reveal genetic determinants of susceptibility to COVID-19 severity in the population and further explore potential immune-related factors, we performed a genome-wide association study on 284 confirmed COVID-19 patients (cases) and 95 healthy individuals (controls). We compared cases and controls of European (EUR) ancestry and African American (AFR) ancestry separately. To further exploring the linkage between HLA and COVID-19 severity, we applied fine-mapping analysis to dissect the HLA association with mild and severe cases.
2023-01-17 | GSE211972 | GEO
Project description:Since the beginning of the SARS-CoV-2 pandemic, COVID-19 has appeared as a unique disease with unconventional tissue and systemic immune features. While COVID-19 severe forms share clinical and laboratory aspects with various pathologies such as hemophagocytic lymphohistiocytosis, sepsis or cytokine release syndrome, their exact nature remains unknown. This is severely impeding the ability to treat patients facing severe stages of the disease. To this aim, we performed an in-depth, single-cell RNA-seq analysis of more than 150.000 immune cells isolated from matched blood samples and broncho-alveolar lavage fluids of COVID-19 patients and healthy controls, and integrated it with clinical, immunological and functional ex vivo data. We unveiled an immune signature of disease severity that correlated with the accumulation of naïve lymphoid cells in the lung and an expansion and activation of myeloid cells in the periphery. Moreover, we demonstrated that myeloid-driven immune suppression is a hallmark of COVID-19 evolution and arginase 1 expression is significantly associated with monocyte immune regulatory features. Noteworthy, we found monocyte and neutro-phil immune suppression loss associated with fatal clinical outcome in severe patients. Additionally, our analysis discovered that the strongest association of the patients clinical outcome and immune phenotype is the lung T cell response. We found that patients with a robust CXCR6+ effector memory T cell response have better outcomes. This result is line with the rs11385942 COVID-19 risk allele, which is in proximity to the CXCR6 gene and suggest effector memory T cell are a primary feature in COVID-19 patients. By systemically quantifying the viral landscape in the lung of severe patients, we indeed identified Herpes-Simplex-Virus 1 (HSV-1) as a potential opportunistic virus in COVID-19 patients. Lastly, we observed an unexpectedly high SARS-CoV-2 viral load in an immuno-compromised patient, allowing us to study the SARS-CoV-2 in-vivo life cycle. The development of my-eloid dysfunctions and the impairment of lymphoid arm establish a condition of immune paralysis that supports secondary bacteria and virus infection and can progress to “immune silence” in patients facing death.
2021-01-27 | GSE157344 | GEO
Project description:Life-threatening thrombotic events and neurological symptoms are prevalent in COVID-19 and are persistent in patients with long COVID experiencing post-acute sequelae of SARS-CoV-2 infection1,2,3,4. Despite the clinical evidence1,5,6,7, the underlying mechanisms of coagulopathy in COVID-19 and its consequences in inflammation and neuropathology remain poorly understood and treatment options are insufficient. Fibrinogen, the central structural component of blood clots, is abundantly deposited in the lungs and brains of patients with COVID-19, correlates with disease severity and is a predictive biomarker for post-COVID-19 cognitive deficits1,5,8,9,10. Here we show that fibrin binds to the SARS-CoV-2 spike protein, forming proinflammatory blood clots that drive systemic thromboinflammation and neuropathology in COVID-19. Fibrin, acting through its inflammatory domain, is required for oxidative stress and macrophage activation in the lungs, whereas it suppresses natural killer cells, after SARS-CoV-2 infection. Fibrin promotes neuroinflammation and neuronal loss after infection, as well as innate immune activation in the brain and lungs independently of active infection. A monoclonal antibody targeting the inflammatory fibrin domain provides protection from microglial activation and neuronal injury, as well as from thromboinflammation in the lung after infection. Thus, fibrin drives inflammation and neuropathology in SARS-CoV-2 infection, and fibrin-targeting immunotherapy may represent a therapeutic intervention for patients with acute COVID-19 and long COVID.
2024-06-28 | GSE268810 | GEO
Project description:Life-threatening thrombotic events and neurological symptoms are prevalent in COVID-19 and are persistent in patients with long COVID experiencing post-acute sequelae of SARS-CoV-2 infection1,2,3,4. Despite the clinical evidence1,5,6,7, the underlying mechanisms of coagulopathy in COVID-19 and its consequences in inflammation and neuropathology remain poorly understood and treatment options are insufficient. Fibrinogen, the central structural component of blood clots, is abundantly deposited in the lungs and brains of patients with COVID-19, correlates with disease severity and is a predictive biomarker for post-COVID-19 cognitive deficits1,5,8,9,10. Here we show that fibrin binds to the SARS-CoV-2 spike protein, forming proinflammatory blood clots that drive systemic thromboinflammation and neuropathology in COVID-19. Fibrin, acting through its inflammatory domain, is required for oxidative stress and macrophage activation in the lungs, whereas it suppresses natural killer cells, after SARS-CoV-2 infection. Fibrin promotes neuroinflammation and neuronal loss after infection, as well as innate immune activation in the brain and lungs independently of active infection. A monoclonal antibody targeting the inflammatory fibrin domain provides protection from microglial activation and neuronal injury, as well as from thromboinflammation in the lung after infection. Thus, fibrin drives inflammation and neuropathology in SARS-CoV-2 infection, and fibrin-targeting immunotherapy may represent a therapeutic intervention for patients with acute COVID-19 and long COVID.
2024-06-28 | GSE268812 | GEO