Monocyte-mediated thrombosis linked to circulating tissue factor and immune-paralysis in COVID-19
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1036593 | ENA |
REPOSITORIES: ENA
Dataset's files
| 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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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.
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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.
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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.
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Project description:Arterial and venous (A/V) thrombosis constitutes the greatest source of morbidity and mortality worldwide. Long considered as distinct entities, accumulating evidence indicates that A/V thrombosis can occur in the same populations suggesting that common mechanisms are likely operative. Although hyperactivation of the immune system is a common forerunner to the genesis of thrombotic events in both vascular systems, the key molecular control points remain poorly understood. Consequently, anti-thrombotic therapies targeting the immune system for therapeutic gain are lacking. Here we show that neutrophils are key effectors of both A/V thrombosis and can be targeted via novel immunoregulatory nanoparticles. Using antiphopholipid antibody syndrome (APS) as a model for devastating A/V thrombosis, we identified the transcription factor Krüppel-like factor 2 (KLF2) as a key regulator of neutrophil activation. Upon activation via genetic loss of KLF2 or administration of antiphospholipid antibodies, neutrophils cluster P-selectin glycoprotein ligand 1 (PSGL-1) via cortical actin remodeling, thereby increasing adhesion potential at thrombosis sites. Targeting clustered PSGL-1 using designer nanoparticles attenuates neutrophil-mediated A/V thrombosis in APS and KLF2 knockout models, illustrating the importance and feasibility of targeting activated neutrophils to prevent pathological thrombosis. Together, our results demosntrate a role for activated neutrophils to prevent pathological thrombosis. Together, our results demonstrate a role for activated neutorphils in both arterial and venous thrombosis and identify key molecular events that serve as potential targets for therapeutics against diverse causes of immunothrombosis.
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