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Monocyte-mediated thrombosis linked to circulating tissue factor and immune-paralysis in COVID-19

ABSTRACT: Monocyte-mediated thrombosis linked to circulating tissue factor and immune-paralysis in COVID-19

PROVIDER: PRJNA1036593 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26705739.fastq.gz	Fastqsanger.gz
	SRR26705740.fastq.gz	Fastqsanger.gz
	SRR26705741.fastq.gz	Fastqsanger.gz
	SRR26705742.fastq.gz	Fastqsanger.gz
	SRR26705743.fastq.gz	Fastqsanger.gz

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Monocyte-mediated thrombosis linked to circulating tissue factor and immune-paralysis in COVID-19

Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections cause coronavirus disease 2019 (COVID-19) and are associated with inflammation and coagulopathy and high incidence of thrombosis. Myeloid cells (Mϕ) help coordinate the initial immune response in COVID-19. Although we appreciate that Mϕ lie at the nexus of inflammation and thrombosis, the mechanisms that unite the two in COVID-19 remain largely unknown. In this study, we employed systems biology approaches including proteomics, transcriptomics, and mass cytometry to define the circulating proteome and circulating immune cell phenotypes in subjects with COVID-19. In a cohort of COVID-19 subjects (n=35), circulating markers of inflammation (CCL23, IL-6) and vascular dysfunction (ACE2, tissue factor [TF]) were elevated in subjects with severe compared with mild COVID-19. Additionally, although the total white blood cell (WBC) counts were similar between COVID-19 groups, CD14+ monocytes from severe COVID-19 subjects expressed more TF. At baseline, transcriptomics demonstrated increased IL-6, CCL3, ACOD1, C5AR1, C5AR2, and TF in severe COVID-19 subjects compared with controls. Using “stress” transcriptomics, we found that circulating immune cells from severe COVID-19 subjects had evidence of profound immune paralysis with greatly reduced transcriptional activation and release of inflammatory markers in response to Toll-like receptor (TLR) activation. Finally, sera from severe (but not mild) COVID-19 subjects activated human monocytes and induced TF expression. Taken together, these observations further elucidate the pathological mechanisms that underlie immune dysfunction and coagulation abnormalities in COVID-19, contributing to our growing understanding of SARS-CoV-2 infections that could also be leveraged to develop novel diagnostic and therapeutic strategies.

2024-01-23 | GSE247186 | GEO

Lipoprotein(a) integrates monocyte-mediated thrombosis and inflammation in atherosclerotic cardiovascular disease

Project description:Although therapies for atherosclerotic cardiovascular disease (ASCVD) have advanced, substantial residual risk of cardiovascular (CV) events remains. Lipoprotein (a) [Lp(a)] is a low-density lipoprotein (LDL) particle that is causally linked to both ASCVD and CV events. Lp(a) is thought to drive ASCVD through multiple mechanisms including its effects on cholesterol accumulation, inflammation, and thrombosis. Although the associations between Lp(a) and ASCVD drivers are clear, the mechanisms that integrate Lp(a)-mediated cholesterol accumulation, inflammation, and thrombosis remain largely unknown. In this study, we employed systems biology approaches consisting of proteomics, transcriptomics, and mass cytometry to define the immune cellular and molecular phenotypes in ASCVD subjects with high and low Lp(a) levels and the mechanisms through which Lp(a) mediates monocyte activation. In a cohort of stable ASCVD subjects (n=64 [41 with high Lp(a) and 23 with low Lp(a]), we found that circulating markers of inflammation (CCL28, IL-17D) and vascular dysfunction (BNP), tissue factor [TF]) was elevated in subjects with high Lp(a) levels compared with those with low Lp(a) levels. Additionally, although total monocytes levels and hs-CRP levels were similar between the groups, CD14+ monocytes from ASCVD subjects with an elevated Lp(a) were primed and expressed more TF at baseline and in response to stress. Mechanistically, we found that Lp(a) itself can activate monocytes through Toll-like receptors (TLR) and nuclear factor kappa B (NFκB) signaling, driving both the induction of TF and TF activity. Overall, these studies are the first to link Lp(a) to monocyte-mediated inflammation and thrombosis, demonstrating a novel mechanism through TLR2, NFκB, and monocyte TF which Lp(a) amplifies immunothrombotic risk.

2025-07-16 | GSE253997 | GEO

Lipoprotein(a) integrates monocyte-mediated thrombosis and inflammation in atherosclerotic cardiovascular disease

Project description:Lipoprotein(a) integrates monocyte-mediated thrombosis and inflammation in atherosclerotic cardiovascular disease

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The life-saving benefit of dexamethasone in severe COVID-19 is linked to a reversal of monocyte dysregulation

Project description:Dexamethasone is a life-saving treatment for severe COVID-19, yet its mechanism of action is unknown, and many patients deteriorate or die despite timely treatment initiation. Here, we identify dexamethasone treatment-induced cellular and molecular changes associated with improved survival in COVID-19 patients. We observed a reversal of transcriptional hallmark signatures in monocytes associated with severe COVID-19 and the induction of a monocyte substate characterized by the expression of glucocorticoid-response genes. These molecular responses to dexamethasone were detected in circulating and pulmonary monocytes, and they were directly linked to survival. Monocyte single-cell RNA sequencing (scRNA-seq)-derived signatures were enriched in whole blood transcriptomes of patients with fatal outcome in two independent cohorts, highlighting the potential for identifying non-responders refractory to dexamethasone. Our findings link the effects of dexamethasone to specific immunomodulation and reversal of monocyte dysregulation, and they highlight the potential of single-cell omics for monitoring in vivo target engagement of immunomodulatory drugs and for patient stratification for precision medicine approaches.

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Absence of COVID-19-associated Changes in Coagulation and Thrombosis in the Ferret Model

Project description:Many patients who are diagnosed with coronavirus disease 2019 (COVID-19) suffer from venous thromboembolic complications despite the use of stringent anticoagulant prophylaxis. Studies on the exact mechanism(s) underlying thrombosis in COVID-19 are limited as animal models commonly used to study venous thrombosis pathophysiology (i.e. rats and mice) are naturally not susceptible to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Ferrets are susceptible to SARS-CoV-2 infection, successfully used to study virus transmission, and were previously used to study activation of coagulation and thrombosis during influenza virus infection. Here, we used plasma and lung material from SARS-CoV-2-inoculated ferrets to explore their use in studying COVID-19-associated changes in coagulation and thrombosis. Lungs of ferrets inoculated intranasally with SARS-CoV-2 demonstrated alveolar septa that were mildly expanded by macrophages, and diffuse interstitial histiocytic pneumonia. However, no macroscopical or microscopical evidence of vascular thrombosis in the lungs of SARS-CoV-2-inoculated ferrets was found. Longitudinal plasma profiling using a mass spectrometry-based approach revealed minor differences in plasma protein profiles in SARS-CoV-2-inoculated ferrets up to 2 weeks post-infection. Apart from fibrinogen, the majority of plasma coagulation factors were stable and demonstrated a low coefficient of variation. We conclude that while ferrets are an essential and well-suited animal model to study SARS-CoV-2 transmission, their use to study SARS-CoV-2-related changes relevant to thrombotic disease is limited.

2022-07-19 | PXD027582 | Pride

Circulating monocytes associated with anti-PD-1 resistance in human biliary cancer induce T cell paralysis

Project description:Circulating monocytes associated with anti-PD-1 resistance in human biliary cancer induce T cell paralysis

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Transcriptomic profile of circulating monocyte subsets in active versus latent tuberculosis

Project description:Transcriptomic profile of circulating monocyte subsets in active versus latent tuberculosis

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Tumor-derived Tissue Factor Activates Coagulation and Enhances Thrombosis in a Mouse Xenograft Model of Human Pancreatic Cancer

Project description:Cancer patients often have an activated clotting system and are at increased risk for venous thrombosis. In this study, we analyzed tissue factor (TF) expression in four different human pancreatic tumor cell lines for the purpose of producing derivative tumors in vivo. We found that two of the lines expressed TF and released TF-positive microparticles (MPs) into the culture medium. The majority of TF protein in the culture medium was associated with MPs. Importantly, only TF-positive cell lines activated coagulation in nude mice, and this activation was abolished by an anti-human TF antibody. Of the two TF-positive lines only one produced detectable levels of human MP TF activity in the plasma when grown orthotopically in nude mice. Surprisingly, <5% of human TF protein in plasma from tumor-bearing mice was associated with MPs. Mice with TF-positive tumors and elevated levels of circulating TF-positive MPs had increased thrombosis in a saphenous vein model. In contrast, we observed no difference in thrombus weight between tumor bearing and control mice in an inferior vena cava stenosis model. Our studies suggest that in a xenograft mouse model tumor TF activates coagulation, whereas TF on circulating MPs may trigger venous thrombosis.

2012-07-12 | GSE37575 | GEO

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