IMMUNE DYSREGULATION FOLLOWING INFECTION BY THE NEW CORONAVIRUS SARS-CoV-2 (COVID-19) A NEW DISEASE ENTITY
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PROVIDER: PRJNA851448 | ENA |
REPOSITORIES: ENA
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Project description:Severe pneumonia by the novel coronavirus (COVID-19 infection) is mediated through immune dysregulation. It was studied if this dysregulation persists after recovery and if it is linked to the manifestation of post-covid syndrome (PCS). Patients who had been hospitalized for COVID-19 pneumonia 3 to 6 months ago during two different time periods and matched comparators were the derivation cohort (n=46, September-October 2020) and the validation cohort (n=484, April-July 2021) respectively. Peripheral blood mononuclear cells (PBMCs) were isolated for culture and cytokine stimulation. Patients provided answers to two health questionnaires allowing classification into PCS and were also subject to lung function tests (LFT). The primary endpoint was the modulation of the production of interleukin (IL)-1b and IL-6 from monocytes and among secondary, the modulation of adaptive immune response and the development of PCS. Increased production of IL-1b (p<0.001) and IL-6 (p<0.001) was found in both study periods compared to control. There was increase of pro-inflammatory Th1 responses over anti-inflammatory Th2 responses and attenuation of the T17 response. PCS was manifested in 22% of patients, grouped into three groups of symptoms. Fatigue was associated with the predominance of Th2 responses and abnormal LFT with overproduction of IL-1b and IL-6. Immune dysregulation is apparent after three months post COVID-19 pneumonia with main features the hyper-production of IL-1β and IL-6 by circulating monocytes, the increase of the Th1/Th2 ratio and the attenuation of T17 response.
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Project description:Aging is identified as a significant risk factor for severe coronavirus disease-2019 (COVID-19), often resulting in profound lung damage and mortality. Yet, the biological relationship between aging, aging-related comorbidities, and COVID-19 remains incompletely understood. This study aimed to elucidate the age-related COVID19 pathogenesis using a Hutchinson-Gilford progeria syndrome (HGPS) mouse model with humanized ACE2 receptors. Pathological features were compared between young, aged, and HGPS hACE2 mice following SAR-CoV-2 challenge. We demonstrated that young mice display robust interferon response and antiviral activity, whereas this response is attenuated in aged mice. Viral infection in aged mice results in severe respiratory tract bleeding, likely contributing a higher mortality rate. In contrast, HGPS hACE2 mice exhibit milder disease manifestations characterized by minor immune cell infiltration and dysregulation of multiple metabolic processes. Comprehensive transcriptome analysis revealed both shared and unique gene expression dynamics among different mouse groups. Collectively, our studies evaluated the impact of SARS-CoV-2 infection on progeroid syndromes using a HGPS hACE2 mouse model, which holds promise as a valuable tool for investigating COVID-19 pathogenesis in individuals with premature aging.
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Project description:In recent months, Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread throughout the world. COVID-19 patients show mild, moderate or severe symptoms with the latter ones requiring access to specialized intensive care. SARS-CoV-2 infections, pathogenesis and progression have not been clearly elucidated yet, thus forcing the development of many complementary approaches to identify candidate cellular pathways involved in disease progression. Host lipids play a critical role in the virus life, being the double-membrane vesicles a key factor in coronavirus replication. Moreover, lipid biogenesis pathways affect receptor-mediated virus entry at the endosomal cell surface and modulate virus propagation. In this study, targeted lipidomic analysis coupled with proinflammatory cytokines and alarmins measurement were carried out in serum of COVID-19 patients characterized by different severity degree. Serum IL-26, a cytokine involved in IL-17 pathway, TSLP and adiponectin were measured and correlated to lipid COVID-19 patient profiles. These results could be important for the classification of the COVID-19 disease and the identification of therapeutic targets.
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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.
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2010-06-05 | E-GEOD-546 | biostudies-arrayexpress
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:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been identified as the cause of the Coronavirus disease 19 (COVID-19), which was initially reported in December 2019 in China and has since rapidly spread worldwide.
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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.
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Project description:COVID-19 has infected 244 million people globally and evolved several variants with higher infectivity. Drug repurposing could be an efficient and timely means of drug discovery for the pandemic. To date, more than two hundred repurposed SARS-CoV-2 inhibitors have been reported but with moderate efficacy or acute toxicity. Thus, there is a great need to find new effective candidates against SARS-CoV-2, especially the new variants, with good safety profiles. We analyzed 17 hundred published host RNA-seq samples of SARS/MERS/SARS-CoV-2 infection derived from pre-clinical models or patients, together with the reported coronavirus inhibitors to summarize a robust coronavirus-induced host gene expression change signature, which captured biological processes involved in host cell machinery hijacking and immune evasion. Then we searched for drugs potently reversing the infection signature and discovered IMD-0354 as a promising candidate with nanomolar IC50 against SARS-CoV-2 and 6 variants, showing a wide therapeutic window of more than 100-fold. The RNA-seq of IMD-0354 treated cells infected with SARS-CoV-2 reaved that this drug could stimulate type I interferon antiviral response, inhibit viral entry and down-regulate hijacked proteins. This work demonstrated the power of biological big data and the efficiency of a system-based drug discovery approach, which can be used in future pandemic.
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