An aberrant immune-epithelial progenitor niche drives post-viral lung sequelae [mouse]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1110281 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28996054_1.fastq.gz | Fastqsanger.gz | |||
| SRR28996054_2.fastq.gz | Fastqsanger.gz | |||
| SRR28996055_1.fastq.gz | Fastqsanger.gz | |||
| SRR28996055_2.fastq.gz | Fastqsanger.gz | |||
| SRR28996056_1.fastq.gz | Fastqsanger.gz |
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Project description:Respiratory viral infections are being increasingly recognized not just for their acute impact but also as potential triggers of long-term health conditions. The recent COVID-19 pandemic in particular has highlighted the prevalence of this phenomenon, termed Post-Acute Sequelae of SARS-CoV-2 (PASC), which has rapidly evolved into a major public health concern. The underlying cellular and molecular etiology remain poorly defined but growing evidence links PASC to abnormal immune responses and/or impaired organ recovery post infection. Yet, the precise mechanisms linking non-resolving inflammation and impaired tissue repair in the context of PASC remain unclear. With insights from three independent clinical cohorts of PASC patients with abnormal lung function and/or viral infection-mediated pulmonary fibrosis, we established a clinically relevant mouse model of post-viral lung sequelae to investigate the pathophysiology of respiratory PASC. By employing a combination of spatial transcriptomics and imaging, we identified dysregulated interactions between immune cells and epithelial progenitors unique to the fibroproliferation in respiratory PASC. Specifically, we found a central role for lung-resident CD8+ T cell-macrophage interactions in maintaining Krt8hi transitional and ectopic Krt5+ basal cell progenitors, thus impairing alveolar regeneration and driving fibrotic sequelae after acute viral pneumonia. CD8+ T cell derived IFN-γ and TNF stimulated local macrophages to chronically release IL-1β, resulting in the abnormal accumulation of dysplastic epithelial progenitors and lung fibrosis. Notably, therapeutic neutralization of IFN-γ and TNF, or IL-1β after the resolution of acute infection resulted in markedly improved alveolar regeneration and restoration of pulmonary function. Together, our findings implicate an aberrant immune-epithelial progenitor niche in driving respiratory PASC. Moreover, in contrast to other approaches requiring early intervention, we highlight therapeutic strategies to rescue fibrotic disease in the aftermath of respiratory viral infections, addressing the current unmet need in the clinical management of PASC and post-viral disease.
2024-08-25 | GSE267228 | GEO
Project description:Respiratory viral infections are being increasingly recognized not just for their acute impact but also as potential triggers of long-term health conditions. The recent COVID-19 pandemic in particular has highlighted the prevalence of this phenomenon, termed Post-Acute Sequelae of SARS-CoV-2 (PASC), which has rapidly evolved into a major public health concern. The underlying cellular and molecular etiology remain poorly defined but growing evidence links PASC to abnormal immune responses and/or impaired organ recovery post infection. Yet, the precise mechanisms linking non-resolving inflammation and impaired tissue repair in the context of PASC remain unclear. With insights from three independent clinical cohorts of PASC patients with abnormal lung function and/or viral infection-mediated pulmonary fibrosis, we established a clinically relevant mouse model of post-viral lung sequelae to investigate the pathophysiology of respiratory PASC. By employing a combination of spatial transcriptomics and imaging, we identified dysregulated interactions between immune cells and epithelial progenitors unique to the fibroproliferation in respiratory PASC. Specifically, we found a central role for lung-resident CD8+ T cell-macrophage interactions in maintaining Krt8hi transitional and ectopic Krt5+ basal cell progenitors, thus impairing alveolar regeneration and driving fibrotic sequelae after acute viral pneumonia. CD8+ T cell derived IFN-γ and TNF stimulated local macrophages to chronically release IL-1β, resulting in the abnormal accumulation of dysplastic epithelial progenitors and lung fibrosis. Notably, therapeutic neutralization of IFN-γ and TNF, or IL-1β after the resolution of acute infection resulted in markedly improved alveolar regeneration and restoration of pulmonary function. Together, our findings implicate an aberrant immune-epithelial progenitor niche in driving respiratory PASC. Moreover, in contrast to other approaches requiring early intervention, we highlight therapeutic strategies to rescue fibrotic disease in the aftermath of respiratory viral infections, addressing the current unmet need in the clinical management of PASC and post-viral disease.
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Project description:An aberrant immune-epithelial progenitor niche drives post-viral lung sequelae [human]
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Project description:Immune signatures underlying post-acute COVID-19 lung sequelae
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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.
2022-02-01 | E-MTAB-10129 | biostudies-arrayexpress
Project description:Post-acute sequelae of SARS-CoV-2 infection are debilitating, clinically heterogeneous, and of unknown molecular etiology. A transcriptome-wide investigation was performed in acutely infected patients followed clinically into the post-acute period. Distinct gene-expression signatures of post-acute sequelae were already present in whole-blood during acute infection, with innate and adaptive immune cells implicated in different symptoms. Two clusters of sequelae exhibited divergent plasma-cell associated gene-expression patterns. In one cluster, sequelae associated with higher expression of immunoglobulin-related genes in an anti-spike antibody titer-dependent manner. In the other, sequelae associated independently of these titers with lower expression of immunoglobulin-related genes, indicating lower non-specific antibody production in subjects with these sequelae. This relationship between lower total immunoglobulins and sequelae was validated in an external cohort. Altogether, multiple etiologies of post-acute sequelae were already detectable during SARS-CoV-2 infection, directly linking these sequelae with the acute host response to the virus and providing early insights into their development.
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Project description:Although a substantial proportion of severe COVID-19 pneumonia survivors exhibit long-term pulmonary sequalae, the underlying mechanisms or associated local and systemic immune correlates are not known. Here, we have performed high dimensional characterization of the pathophysiological and immune traits of aged COVID-19 convalescents, and correlated the local and systemic immune profiles with pulmonary function and lung imaging. In this cohort of aged COVID-19 convalescents, chronic lung impairment was accompanied by persistent systemic inflammation and respiratory immune alterations. Detailed evaluation of the lung immune compartment revealed dysregulated respiratory CD8+ T cell responses that likely underlie the impaired lung function following acute COVID-19 during aging. Single cell transcriptomic analysis identified the potential pathogenic subsets of respiratory CD8+ T cells causing persistent tissue conditions following COVID-19. Our results have revealed key pathophysiological and immune traits that support the development of lung sequelae following SARS-CoV2 pneumonia during aging, with implications for the treatment of chronic COVID-19 symptoms.
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Project description:Post-acute sequelae of COVID-19 (PASC, "Long COVID") pose a significant global health challenge. The pathophysiology is unknown, and no effective treatments have been found to date. Several hypotheses have been formulated to explain the etiology of PASC, including viral persistence, chronic inflammation, hypercoagulability, and autonomic dysfunction. Here, we propose a mechanism that links all four hypotheses in a single pathway and provides actionable insights for therapeutic interventions. We find that PASC are associated with serotonin reduction. Viral infection and type I interferon-driven inflammation reduce serotonin through three mechanisms: diminished intestinal absorption of the serotonin precursor tryptophan; platelet hyperactivation and thrombocytopenia, which impacts serotonin storage; and enhanced MAO-mediated serotonin turnover. Peripheral serotonin reduction, in turn, impedes the activity of the vagus nerve and thereby impairs hippocampal responses and memory. These findings provide a possible explanation for neurocognitive symptoms associated with viral persistence in Long COVID, which may extend to other post-viral syndromes.
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