Proteomic Analysis of Pleural Effusions from COVID-19 Deceased Patients: Enhanced Inflammatory Markers

Razaghi, Ali; Szakos, Attila; Alouda, Marwa; Bozóky, Béla; Björnstedt, Mikael; Szekeres, L.

doi:10.3390/diagnostics12112789

Cited by 9 publications

(4 citation statements)

References 44 publications

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“…Flt3L, an ideal adjuvant that functions as a cytokine and a growth factor, can activate DCs and lymphocytes to enhance innate and adaptive immune responses. In pleural effusions from deceased COVID-19 patients, Flt3L was found to be elevated . According to plasma profiling, the circulation level of Flt3L increased in patients with severe COVID-19 infection, which was associated with endothelial injury .…”

Section: Discussionmentioning

confidence: 96%

“…In pleural effusions from deceased COVID-19 patients, Flt3L was found to be elevated. 27 According to plasma profiling, the circulation level of Flt3L increased in patients with severe COVID-19 infection, which was associated with endothelial injury. 28 Moreover, Flt3L was found to be correlated with radiological features in bronchial aspirates from critically ill patients with SARS-CoV-2 infection, 29 which contributed to the regulation of pulmonary fibrosis.…”

Section: Discussionmentioning

confidence: 99%

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Potential Immune-Inflammatory Proteome Biomarkers for Guiding the Treatment of Patients with Primary Acute Angle-Closure Glaucoma Caused by COVID-19

Gong,

Fu,

Wang

et al. 2024

J. Proteome Res.

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Primary acute angle-closure glaucoma (PAACG) is a sight-threatening condition that can lead to blindness. With the increasing incidence of COVID-19, a multitude of people are experiencing acute vision loss and severe swelling of the eyes and head. These patients were then diagnosed with acute angle closure, with or without a history of PACG. However, the mechanism by which viral infection causes PACG has not been clarified. This is the first study to explore the specific inflammatory proteomic landscape in SARS-CoV-2-induced PAACG. The expression of 92 inflammation-related proteins in 19 aqueous humor samples from PAACGs or cataract patients was detected using the Olink Target 96 Inflammation Panel based on a highly sensitive and specific proximity extension assay technology. The results showed that 76 proteins were significantly more abundant in the PAACG group than in the cataract group. Notably, the top eight differentially expressed proteins were IL-8, MCP-1, TNFRSF9, DNER, CCL4, Flt3L, CXCL10, and CD40. Generally, immune markers are related to inflammation, macrophage activation, and viral infection, revealing the crucial role of macrophages in the occurrence of PAACGs caused by SARS-CoV-2.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Potential Immune-Inflammatory Proteome Biomarkers for Guiding the Treatment of Patients with Primary Acute Angle-Closure Glaucoma Caused by COVID-19

Gong,

Fu,

Wang

et al. 2024

J. Proteome Res.

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“…PTN was also considered to be a potential biomarker for inflammatory ischemic cardiomyopathy with good ICM recognition [40] . In a proteomic analysis of pleural effusion from dead COVID-19 patients, 182 protein biomarkers including PTN were significantly elevate, indicating immune system overstimulation and cytokine storm [41] . These studies suggested that PTN was involved in the development of some cardiovascular diseases, but its underlying mechanisms are not well understood.…”

Section: Discussionmentioning

confidence: 99%

Integrated single-cell RNA-seq analysis revealed PTN secreted by fibroblasts acting on itself and macrophages via SDC4 ligand in myocardial hypertrophy

Sheng,

Ran,

Guan

et al. 2024

Preprint

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BackgroundHypertrophic cardiomyopathy (HCM) is characterized by massive myocardial hypertrophy, which is the most frequent cause of sudden death and can lead to heart failure (HF) or stroke. The objective of this study was to explore the communication network among various cells in the heart of pathological HCM derived from transverse aortic constriction (TAC) mouse model, and investigate the potential mechanism through data mining, biological informatics analysis, and experimental validation.Methods and ResultsThe integrated analyses including CellChat, Seurat, gene ontology (GO), pseudo-time trajectory analysis, and weighted gene co-expression network analysis (WGCNA) were performed based on the single-cell RNA-seq data (scRNA-seq). In vitrotests were conducted to verify bioinformatic analysis findings through enzyme-linked immunosorbent assay (ELISA), real-time quantitative PCR (RT-qPCR), Edu staining, and transwell assay.In vivotests were also performed to further verify bioinformatic analysis findings by western blot and immunofluorescence assays based on our established TAC mouse model with myocardial hypertrophy. Our results showed that in the heart of TAC mouse, the interaction between cardiac fibroblasts and macrophages was most common, and the increasing pleiotrophin (PTN) secreted by cardiac fibroblasts could promote themselves proliferation or invasion as well as stimulate macrophage activation to release inflammatory cytokines, such as TNF-α, IL-6, Cox-2, Cd83, Egr2, and IL-10 through acting on its ligand recombinant Syndecan 4 (SDC4), which may affect cardiomyocyte normal function and eventually cause HCM. This study first demonstrated that PTN derived from cardiac fibroblasts may act on SDC4 to play crucial role in myocardial hypertrophy, which may be a potential therapeutic targets for patients with pathological HCM.ConclusionsIn this study, the complex interaction network between cardiac fibroblasts and macrophages of TAC mice based on the scRNA-seq data was investigated, and we found that the increasing PTN secreted by cardiac fibroblasts under cardiac pressure overload could promote themselves proliferation or invasion as well as stimulate macrophage activation to release inflammatory cytokines through acting on SDC4 ligand, which may affect cardiomyocyte normal function and eventually cause HCM. In addition, our study suggested that PTN derived from cardiac fibroblasts may act on SDC4 ligand to play crucial role in myocardial hypertrophy, which may be a potential therapeutic targets for patients with pathological HCM.

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“…Noteworthy additional LRIs involved PSAP (PSAP^LRP1) and members of the S100 protein family S100A8 (S100A8^AGER, S100A8^ITGB2) and S100A9 (S100A9^AGER, S100A9^CD68, S100A9^ITGB2), that have been reported to activate macrophages in COVID-19 (Melms et (Amraei et al, 2022). Beyond the mentioned ligand proteins, it is also relevant to mention that the three most frequent receptors involved in the LRIs (Table S1) were CD44, involved in T-cell abundance and fostering of the cytokine storm linked to poor prognosis of COVID-19 patients (Zick, 2022); ITGB1, that associates with the angiotensinconverting enzyme 2 (ACE2) to mediate SARS-CoV-2 entry (Zhang et al, 2022) and regulates ECM remodeling; and LRP1, that is involved in the overproduction of cytokines and chemokines (Zick, 2022) and enriched in those COVID-19 patients that died (Razaghi et al, 2022) or underwent long haul COVID-19 disease (Gu et al, 2023). The NMF factor scores indicating the strength of each factor in each spot are depicted for illustrative examples of VisiumST slide images throughout COVID-19 induced DAD progression and shown in Figure 3C.…”

Section: Spatial Cell-cell Interactions In the Spectrum Of The Diseasementioning

confidence: 99%

Spatial transcriptomics unveils thein situcellular and molecular hallmarks of the lung in fatal COVID-19

Garcia-Prieto,

Musulen,

Davalos

et al. 2024

Preprint

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Severe Coronavirus disease 2019 (COVID-19) induces heterogeneous and progressive diffuse alveolar damage (DAD) highly disrupting lung tissue architecture and homeostasis, hampering disease management leading to fatal outcomes. Characterizing DAD pathophysiology across disease progression is of ultimate importance to better understand the molecular and cellular features driving different DAD patterns and to optimize treatment strategies. To contextualize the interplay between cell types and assess their distribution, spatial transcriptomics (ST) techniques have emerged, allowing unprecedented resolution to investigate spatial architecture of tissues. To this end, post-mortem lung tissue provides valuable insights into cellular composition and their spatial relationships at the time of death. Here, we have leveraged VisumST technology in post-mortem COVID-19 induced acute and proliferative DAD lungs including control samples with normal morphological appearance, to unravel the immunopathological mechanisms underlying DAD, providing novel insights into cellular and molecular communication events driving DAD progression in fatal COVID-19. We report a progressive loss of endothelial cell types, pneumocytes type I and natural killer cells coupled with a continuous increase of myeloid and stromal cells, mostly peribronchial fibroblasts, over disease progression. Spatial organization analysis identified variable cellular compartments, ranging from major compartments defined by cell type lineages in control lungs to increased and more specific compartmentalization including immune-specific clusters across DAD spectrum. Importantly, spatially informed ligand-receptor interaction (LRI) analysis revealed an intercellular communication signature defining COVID-19 induced DAD lungs. Transcription factor (TF) activity enrichment analysis identified TGF-B pathway as DAD driver, highlighting SMAD3 and SMAD7 TFs activity role during lung fibrosis. Integration of deregulated LRIs and TFs activity allowed us to propose a downstream intracellular signaling pathway in peribronchial fibroblasts, suggesting potential novel therapeutic targets. Finally, spatio-temporal trajectories analysis provided insights into the alveolar epithelium regeneration program, characterizing markers of pneumocytes type II differentiation towards pneumocytes type I. In conclusion, we provide a spatial characterization of lung tissue architecture upon COVID-19 induced DAD progression, identifying molecular and cellular hallmarks that may help optimize treatment and patient management.

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Proteomic Analysis of Pleural Effusions from COVID-19 Deceased Patients: Enhanced Inflammatory Markers

Cited by 9 publications

References 44 publications

Potential Immune-Inflammatory Proteome Biomarkers for Guiding the Treatment of Patients with Primary Acute Angle-Closure Glaucoma Caused by COVID-19

Potential Immune-Inflammatory Proteome Biomarkers for Guiding the Treatment of Patients with Primary Acute Angle-Closure Glaucoma Caused by COVID-19

Integrated single-cell RNA-seq analysis revealed PTN secreted by fibroblasts acting on itself and macrophages via SDC4 ligand in myocardial hypertrophy

Spatial transcriptomics unveils thein situcellular and molecular hallmarks of the lung in fatal COVID-19

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