Macrophage expression and prognostic significance of the long pentraxin PTX3 in COVID-19
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ABSTRACT:
PROVIDER: PRJNA672981 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12926701_1.fastq.gz | Fastqsanger.gz | |||
| SRR12926701_2.fastq.gz | Fastqsanger.gz | |||
| SRR12926702_1.fastq.gz | Fastqsanger.gz | |||
| SRR12926702_2.fastq.gz | Fastqsanger.gz | |||
| SRR12926703_1.fastq.gz | Fastqsanger.gz |
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Project description:PTX3 is an essential component of humoral innate immunity, involved in resistance to selected pathogens and in the regulation of inflammation1-3. The present study was designed to assess the presence and significance of PTX3 in COVID-194-7. RNA-seq analysis of peripheral blood mononuclear cells, single-cell bioinformatics analysis and immunohistochemistry of lung autopsy samples revealed that myelomonocytic cells and endothelial cells express high levels of PTX3 in COVID-19 patients. Increased plasma concentrations of PTX3 were detected in 96 COVID-19 patients. PTX3 emerged as a strong independent predictor of 28-day mortality in multivariable analysis, better than conventional markers of inflammation, in hospitalized COVID-19 patients. The prognostic significance of PTX3 abundance for mortality was confirmed in a second independent cohort (54 patients). Thus, circulating and lung myelomonocytic cells and endothelial cells are a major source of PTX3, and PTX3 plasma concentration can serve as an independent strong prognostic indicator of short-term mortality in COVID-19.
2020-10-29 | GSE160351 | GEO
Project description:Prognostic characteristics inform risk stratification in intensive care unit (ICU) patients with coronavirus disease 2019 (COVID-19). We obtained blood samples (n = 474) from hospitalized COVID-19 patients (n = 123), non-COVID-19 ICU sepsis patients (n = 25) and healthy controls (n = 30). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA was detected in plasma or serum (RNAemia) of COVID-19 ICU patients when neutralizing antibody response was low. RNAemia was associated with higher 28-day ICU mortality (hazard ratio [HR], 1.84 [95% CI, 1.22–2.77] adjusted for age and sex). In longitudinal comparisons, COVID-19 ICU patients had a distinct proteomic trajectory associated with RNAemia and mortality. Among COVID-19-enriched proteins, galectin-3 binding protein (LGALS3BP) and proteins of the complement system were identified as interaction partners of SARS-CoV-2 spike glycoprotein. Finally, machine learning identified ‘Age, RNAemia’ and ‘Age, pentraxin-3 (PTX3)’ as the best binary signatures associated with 28-day ICU mortality.
2021-04-26 | PXD024089 | Pride
Project description:Prognostic characteristics inform risk stratification in intensive care unit (ICU) patients with coronavirus disease 2019 (COVID-19). We obtained blood samples (n = 474) from hospitalized COVID-19 patients (n = 123), non-COVID-19 ICU sepsis patients (n = 25) and healthy controls (n = 30). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA was detected in plasma or serum (RNAemia) of COVID-19 ICU patients when neutralizing antibody response was low. RNAemia was associated with higher 28-day ICU mortality (hazard ratio [HR], 1.84 [95% CI, 1.22–2.77] adjusted for age and sex). In longitudinal comparisons, COVID-19 ICU patients had a distinct proteomic trajectory associated with RNAemia and mortality. Among COVID-19-enriched proteins, galectin-3 binding protein (LGALS3BP) and proteins of the complement system were identified as interaction partners of SARS-CoV-2 spike glycoprotein. Finally, machine learning identified ‘Age, RNAemia’ and ‘Age, pentraxin-3 (PTX3)’ as the best binary signatures associated with 28-day ICU mortality.
2021-04-26 | PXD024026 | Pride
Project description:PTX3, as the long member of the pentraxin family, is produced mainly by dendritic cells, macrophages, and endothelial cells in response to inflammation. Growing amount of studies suggest that PTX3 can exert potential contradictory roles in inflammation regulation, antimicrobial resistance, and disease pathogenesis, depending on the tissue context, cellular source, and levels of production. To characterize the potential involvement of PTX3 in macrophage function, transcriptome sequencing (RNA-seq) was performed in human THP1-derived macrophages with PTX3 depletion. Notably,genes enrichment in PI3K/AKT signaling , JAK/STAT signaling and autophagy pathway were observed in PTX3 deficiency macrophages. This study highlights the critical roles of PTX3 on regulation macrophages homeostasis.
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Project description:The pattern recognition receptor long pentraxin-3 (PTX3) plays conflicting roles in cancer by acting as an oncosuppressor or as a pro-tumor mediator depending on tumor context. Triple negative breast cancer (TNBC) represents the most aggressive histotype of breast cancer, characterized by the lack of efficacious therapeutic targets/approaches and poor prognosis. In this study, in silico data and experimental evidences indicate that PTX3 is produced by tumor parenchyma in TNBC and that its expression levels correlate with tumor stage. On this basis, the impact of PTX3 silencing or its overexpression on the tumorigenic potential of TNBC cell lines was analyzed. Gene expression and in vitro results demonstrate that high levels of PTX3 expression confer a high aggressive/proliferative phenotype, fosters stem-like features, and rewires the energy metabolism in TNBC cells. This results in a more tumorigenic potential in vivo when TNBC cells are grafted in immune-compromised and syngeneic animals. Mechanistically, our data reveal a strong positive correlation between PTX3 expression and the antitumor activity of Toll-like receptor 4 (TLR4) inhibition in TBNC, demonstrating for the first time that PTX3-driven TNBC aggressiveness is due to PTX3-mediated activation of TLR4 signaling. Altogether, these data shed light on the role of tumor-produced PTX3 in TNBC and uncover the importance of the PTX3/TLR4 pathway for therapeutic and prognostic exploitation in TNBC.
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Project description:Pattern recognition molecules (PRMs) form an important part of innate immunity and respond to infection and damage via triggering processes such as inflammation. The pentraxin family of soluble PRMs comprises long and short pentraxins, with the former containing unique N-terminal regions unrelated to other proteins or each other. No high-resolution structural information exists about long pentraxins, unlike the short pentraxins where there is an abundance of both X-ray and cryo-electron microscopy (cryoEM) derived structures. This study presents for the first time a high-resolution structure of the prototypical long pentraxin, PTX3. CryoEM yielded a 2.5 Å map of the C-terminal pentraxin domains that revealed a radically different quaternary structure compared to other pentraxins, comprising a glycosylated D4 symmetrical octameric complex stabilised by an extensive disulfide network. The cryoEM map indicated α-helices that extended N-terminal of the pentraxin domains that were not fully resolved. AlphaFold was used to predict the remaining N-terminal structure of the octameric PTX3 complex, revealing two long tetrameric coiled coils with two hinge regions, which was validated using classification of cryoEM 2D averages. The resulting hybrid cryoEM/AlphaFold structure allowed mapping of ligand binding sites, such as C1q and FGF2, as well as rationalisation of previous biochemical data. Given the relevance of PTX3 in conditions ranging from COVID-19 prognosis, cancer progression and female infertility, this structure could be used to inform the understanding and rational design of therapies for these disorders and processes.
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Project description:In managing patients with coronavirus disease 2019 (COVID-19), early identification of those at high risk and real-time monitoring of disease progression to severe COVID-19 is a major challenge. We aimed to identify early prognostic protein markers and to discover surrogate protein markers that effectively reflect the clinical progression of the disease. We performed in-depth proteome profiling on 137 sera, longitudinally collected from 25 patients with COVID-19 (non-severe patients, n = 13; patients who progressed to severe COVID-19, n = 12). We identified 11 potential biomarkers, including the novel markers IGLV3-19 and BNC2, as early prognostic indicators of severe COVID-19. These potential biomarkers are mainly involved in biological processes associated with humoral immune response, interferon signalling, acute phase response, lipid metabolism, and platelet degranulation. We further revealed that the longitudinal changes of 40 proteins persistently increased or decreased as the disease progressed to severe COVID-19. These 40 potential biomarkers could effectively reflect the clinical progression of the disease. This study supports the development of protein biomarkers, which might enable better predicting and monitoring progression to severe COVID-19.
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Project description:The human long pentraxin PTX3 has complex regulatory roles at the crossroad of innate immunity, inflammation, and tissue repair. PTX3 can be produced by various cell types, including vascular endothelial cells (ECs), in response to pro-inflammatory cytokines or bacterial molecules. But PTX3 has also been involved in the regulation of cardiovascular biology, even if contrasting results have been so far provided in both preclinical and clinical research. Therefore, we compared the proteomic profiles of human ECs isolated from umbilical cords (Human Umbilical Vein ECs, HUVECs), and we identified 19 proteins more abundant in the proteome of control ECs and 23 proteins more expressed in PTX3 silenced cells.
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Project description:The coronavirus disease 19 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) posts a challenge for the understanding of factors affecting disease severity and the identification of prognostic biomarkers and physiological processes relevant for the development of new diagnostic and therapeutic interventions to contribute to the control of this pandemic. To address this challenge, in this study we used a quantitative proteomics together with multiple data analysis algorithms to characterize serum protein profiles in five cohorts from healthy to SARS-CoV-2-infected asymptomatic, recovered, nonsevere and severe individuals. The results corroborated previous findings, but the analysis was focused on novel disease processes and biomarkers. Our results contributed to the characterization of SARS-CoV-2-host molecular interactions and provided protein prognostic biomarkers and physiological disorders associated with COVID-19 with potential implications for the development of new diagnostic and therapeutic interventions to contribute to the control of this pandemic.
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