Circulating fibroblasts present neutrophil-like features in severe COVID-19 cases revealed by single-cell landscape analyses.
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ABSTRACT:
SUBMITTER: Liu X
PROVIDER: S-EPMC10041865 | biostudies-literature | 2023 Mar
REPOSITORIES: biostudies-literature
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Circulating fibroblasts present neutrophil-like features in severe COVID-19 cases revealed by single-cell landscape analyses.
Liu Xiangjun X Gui Jingang J Wang Xiaolin X Wang Xiaolin X
Genes & diseases 20230327
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Project description:BackgroundElucidating the modes of action (MoAs) of drugs and drug candidate compounds is critical for guiding translation from drug discovery to clinical application. Despite the development of several data-driven approaches for predicting chemical-disease associations, the molecular cues that organize the epigenetic landscape of drug responses remain poorly understood.ResultsWith the use of a computational method, we attempted to elucidate the epigenetic landscape of drug responses, in terms of transcription factors (TFs), through large-scale ChIP-seq data analyses. In the algorithm, we systematically identified TFs that regulate the expression of chemically induced genes by integrating transcriptome data from chemical induction experiments and almost all publicly available ChIP-seq data (consisting of 13,558 experiments). By relating the resultant chemical-TF associations to a repository of associated proteins for a wide range of diseases, we made a comprehensive prediction of chemical-TF-disease associations, which could then be used to account for drug MoAs. Using this approach, we predicted that: (1) cisplatin promotes the anti-tumor activity of TP53 family members but suppresses the cancer-inducing function of MYCs; (2) inhibition of RELA and E2F1 is pivotal for leflunomide to exhibit antiproliferative activity; and (3) CHD8 mediates valproic acid-induced autism.ConclusionsOur proposed approach has the potential to elucidate the MoAs for both approved drugs and candidate compounds from an epigenetic perspective, thereby revealing new therapeutic targets, and to guide the discovery of unexpected therapeutic effects, side effects, and novel targets and actions.
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Project description:Moyamoya disease (MMD) is a cerebrovascular disorder marked by progressive arterial narrowing, categorized into six stages known as Suzuki stages based on angiographic features. Growing evidence indicates a pivotal role of systemic immune and inflammatory responses in the initiation and advancement of MMD. This study employs high-dimensional mass cytometry to reveal the immunophenotypic characteristics of peripheral blood immune cells (PBMCs) at various Suzuki stages, offering insights into the progression of MMD. PBMC samples from eight patients with early-stage MMD (Suzuki stages II and III) and eight patients with later-stage MMD (Suzuki stages IV, V, and VI) were analyzed using high-dimensional mass cytometry to evaluate the frequency and phenotype of immune cell subtypes. We identified 15 cell clusters and found that the immunological features of early-stage MMD and later-stage MMD are composed of cluster variations. In this study, we confirmed that, compared to later-stage MMD, the early-stage MMD group exhibits an increase in non-classical monocytes. As the Suzuki stage level increases, the proportions of plasmacytoid DCs and monocyte-derived DCs decrease. Furthermore, T cells, monocytes, DCs, and PMN-MDSCs in the early-stage MMD group show activation of the canonical NF-κB signaling pathway. We summarized and compared the similarities and differences between early-stage MMD patients and later-stage MMD patients. There is a potential role of circulating immune dysfunction and inflammatory responses in the onset and development of MMD.
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Project description:PurposeA prompt and effective immune response is required for clearance of pathogens but exaggerated states of inflammation can cause extensive collateral damage to the host. We have previously used a rapid near-patient assay that measures the functional capacity of neutrophils to produce reactive oxygen species (ROS) to show that values are elevated in patients with severe COVID-19 or sepsis. Here, we assess the utility of longitudinal ROS measurements to monitor and predict mortality outcome for patients with COVID-19 infection being treated in an ICU setting.MethodsWe used the Leukocyte ImmunoTest™ (LIT™) to quantify neutrophil ROS release using a small volume (10 µL) of capillary blood in a portable, rapid (10-min) format.ResultsROS values (LIT score) and ROS levels assessed in relation to neutrophil count (LIT/N) were both markedly elevated in the patient group. Furthermore, these correlated strongly with peripheral neutrophil count and CRP value. Serial measurement of neutrophil or CRP values were not able to reliably predict mortality within the study. In contrast, LIT and LIT/N values started to decline at 7 and 5 days, respectively, in patients who survived ICU admission and this increment increased further thereafter.ConclusionsThis study raises the possibility of LIT and LIT/N to be used as a predictive clinical tool for patients with severe COVID-19 and argues for its assessment to inform on prognosis, and potentially guide treatment pathways, in other disorders associated with neutrophil activation.Take-home messageA longitudinal study of 44 severe COVID-19 patients in the ICU of a leading teaching hospital has demonstrated the prognostic potential of a rapid bedside assay of neutrophil-derived reactive oxygen species (ROS). Assessment of changes in ROS production, as measured using the Leukocyte ImmunoTest™, shows that ROS production generally declined back to normal levels for patients who survived, but remained elevated for those patients who did not survive.
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Project description:BackgroundNeutrophil plays a pivotal role in the management of Klebsiella pneumoniae infection. Delineate the clinical characteristics and prognostic utility of neutrophil in severe patients with K. pneumoniae infection are crucial for clinical management and prognostic assessment.MethodsK. pneumoniae patients with different infection sites were enrolled from Medical Information Mart for Intensive Care IV and eICU Collaborative Research Database. Temporal variations of neutrophil counts within 30 days of clinical onset were examined using locally weighted scatterplot smoothing curves. Logistic regression analysis was performed to assess the relationship between neutrophil counts and hospital mortality.ResultsA total of 1,705 patients caused by K. pneumonia were included in the study. The non-survivor group exhibited a comparatively older age and a higher proportion of K. pneumoniae infections originating from respiratory and bloodstream sources compared to the survivor group (38.4% vs 21.1%, p<0.0001, and 15.1% vs 10.3%, p=0.021). Patients combined with multiple drug resistance strains, respiratory infection, liver disease, and above 60 years exhibited a specific dynamic process of neutrophil levels. Neutrophils counts peaked at admission and 1-2 weeks later. There was a 'U'-shaped relationship between neutrophil counts and hospital mortality.ConclusionsNeutrophils in K. pneumoniae infected patients have distinctive features and dynamic clinical trajectories. Close monitoring of severe patients infected with K. pneumoniae upon admission and during the first 1-2 weeks after admission is of utmost importance, particularly for patients with a neutrophil count exceeding 8.0×109/L.
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