Platelet Phenotype Analysis of COVID-19 Patients Reveals Progressive Changes in the Activation of Integrin αIIbβ3, F13A1, the SARS-CoV-2 Target EIF4A1 and Annexin A5

Ercan, Huriye; Schrottmaier, Waltraud C.; Pirabe, Anita; Schmuckenschlager, Anna; Pereyra, David; Santol, Jonas; Pawelka, Erich; Traugott, Marianna; Schörgenhofer, Christian; Seitz, Tamara; Karolyi, Mario; Yang, Jing; Jilma, Bernd; Zoufaly, Alexander; Assinger, Alice; Zellner, Maria

doi:10.3389/fcvm.2021.779073

Cited by 21 publications

(17 citation statements)

References 73 publications

(84 reference statements)

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“…RNA sequencing of platelets in COVID-19 patients has revealed an altered transcriptional profile with enrichment in the pathways of antigen presentation, protein ubiquitination and mitochondrial dysfunction ( 12 ). Phenotypic analysis of platelets in COVID-19 demonstrated that platelets undergo a series of functional and biochemical changes most pronounced in patients with severe disease ( 20 ). In addition, SARS-CoV-2 has been shown to associate with ( 21 ) and bind ACE2 receptors on the platelet surface ( 22 ), whereas other studies have demonstrated that platelets can internalize SARS-CoV-2 virions in a process that contributes to their hyperactivated state ( 23 ).…”

Section: Introductionmentioning

confidence: 99%

Signaling Through FcγRIIA and the C5a-C5aR Pathway Mediate Platelet Hyperactivation in COVID-19

Apostolidis¹,

Sarkar²,

Giannini³

et al. 2022

Front. Immunol.

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Patients with COVID-19 present with a wide variety of clinical manifestations. Thromboembolic events constitute a significant cause of morbidity and mortality in patients infected with SARS-CoV-2. Severe COVID-19 has been associated with hyperinflammation and pre-existing cardiovascular disease. Platelets are important mediators and sensors of inflammation and are directly affected by cardiovascular stressors. In this report, we found that platelets from severely ill, hospitalized COVID-19 patients exhibited higher basal levels of activation measured by P-selectin surface expression and had poor functional reserve upon in vitro stimulation. To investigate this question in more detail, we developed an assay to assess the capacity of plasma from COVID-19 patients to activate platelets from healthy donors. Platelet activation was a common feature of plasma from COVID-19 patients and correlated with key measures of clinical outcome including kidney and liver injury, and APACHEIII scores. Further, we identified ferritin as a pivotal clinical marker associated with platelet hyperactivation. The COVID-19 plasma-mediated effect on control platelets was highest for patients that subsequently developed inpatient thrombotic events. Proteomic analysis of plasma from COVID-19 patients identified key mediators of inflammation and cardiovascular disease that positively correlated with in vitro platelet activation. Mechanistically, blocking the signaling of the FcγRIIa-Syk and C5a-C5aR pathways on platelets, using antibody-mediated neutralization, IgG depletion or the Syk inhibitor fostamatinib, reversed this hyperactivity driven by COVID-19 plasma and prevented platelet aggregation in endothelial microfluidic chamber conditions. These data identified these potentially actionable pathways as central for platelet activation and/or vascular complications and clinical outcomes in COVID-19 patients. In conclusion, we reveal a key role of platelet-mediated immunothrombosis in COVID-19 and identify distinct, clinically relevant, targetable signaling pathways that mediate this effect.

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Section: Introductionmentioning

confidence: 99%

Signaling Through FcγRIIA and the C5a-C5aR Pathway Mediate Platelet Hyperactivation in COVID-19

Apostolidis¹,

Sarkar²,

Giannini³

et al. 2022

Front. Immunol.

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“…The protein αIIbβ3 is a heterodimeric platelet receptor that plays an essential role in platelet aggregation (Ma et al ., 2007). A previous study showed that the level of αIIbβ3 activation on platelets from non-surviving COVID-19 patients decreased compared to survivors (Ercan et al ., 2021, 5). The mechanism for the decline in αIIbβ3 in severe COVID-19 patients was unknown.…”

Section: Discussionmentioning

confidence: 99%

EMoMiS: A Pipeline for Epitope-based Molecular Mimicry Search in Protein Structures with Applications to SARS-CoV-2

Stebliankin

Baral

Balbin

et al. 2022

Preprint

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Epitope-based molecular mimicry occurs when an antibody cross-reacts with two different antigens due to structural and chemical similarities. Molecular mimicry between proteins from two viruses can lead to beneficial cross-protection when the antibodies produced by exposure to one also react with the other. On the other hand, mimicry between a protein from a pathogen and a human protein can lead to auto-immune disorders if the antibodies resulting from exposure to the virus end up interacting with host proteins. While cross-protection can suggest the possible reuse of vaccines developed for other pathogens, cross-reaction with host proteins may explain side effects. There are no computational tools available to date for a large-scale search of antibody cross-reactivity. We present a comprehensive Epitope-based Molecular Mimicry Search (EMoMiS) pipeline for computational molecular mimicry searches. EMoMiS, when applied to the SARS-CoV-2 Spike protein, identified eight examples of molecular mimicry with viral and human proteins. These findings provide possible explanations for (a) differential severity of COVID-19 caused by cross-protection due to prior vaccinations and/or exposure to other viruses, and (b) commonly seen COVID-19 side effects such as thrombocytopenia and thrombophilia. Our findings are supported by previously reported research but need validation with laboratory experiments. The developed pipeline is generic and can be applied to find mimicry for novel pathogens. It has applications in improving vaccine design. The developed Epitope-based Molecular Mimicry Search Pipeline (EMoMiS) is available from https://biorg.cs.fiu.edu/emomis/.

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“…Dysregulation of this gene pathway may contribute to downstream effects of antigen presentation and sustained T cell activation [75]. Lastly, the 5 cap of SARS CoV-2 is recognized by Eukaryotic initiation factor 4A-1 (EIF4A1) [76] and is known to be significantly increased in the platelet proteome of COVID-19 patients thought to affect viral replication and downstream activation of platelets, resulting in thrombotic microangiopathy and increased mortality [77]. Collectively, the results of our WGCNA analysis identified a substantial network of dysregulated genes with many downstream effects that are linked to clinicopathologic data.…”

Section: Discussionmentioning

confidence: 99%

SARS CoV-2 (Delta Variant) Infection Kinetics and Immunopathogenesis in Domestic Cats

Selvan

Gunasekara

Xiao

et al. 2022

Viruses

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Continued emergence of SARS-CoV-2 variants highlights the critical need for adaptable and translational animal models for acute COVID-19. Limitations to current animal models for SARS CoV-2 (e.g., transgenic mice, non-human primates, ferrets) include subclinical to mild lower respiratory disease, divergence from clinical COVID-19 disease course, and/or the need for host genetic modifications to permit infection. We therefore established a feline model to study COVID-19 disease progression and utilized this model to evaluate infection kinetics and immunopathology of the rapidly circulating Delta variant (B.1.617.2) of SARS-CoV-2. In this study, specific-pathogen-free domestic cats (n = 24) were inoculated intranasally and/or intratracheally with SARS CoV-2 (B.1.617.2). Infected cats developed severe clinical respiratory disease and pulmonary lesions at 4- and 12-days post-infection (dpi), even at 1/10 the dose of previously studied wild-type SARS-CoV-2. Infectious virus was isolated from nasal secretions of delta-variant infected cats in high amounts at multiple timepoints, and viral antigen was co-localized in ACE2-expressing cells of the lungs (pneumocytes, vascular endothelium, peribronchial glandular epithelium) and strongly associated with severe pulmonary inflammation and vasculitis that were more pronounced than in wild-type SARS-CoV-2 infection. RNA sequencing of infected feline lung tissues identified upregulation of multiple gene pathways associated with cytokine receptor interactions, chemokine signaling, and viral protein–cytokine interactions during acute infection with SARS-CoV-2. Weighted correlation network analysis (WGCNA) of differentially expressed genes identified several distinct clusters of dysregulated hub genes that are significantly correlated with both clinical signs and lesions during acute infection. Collectively, the results of these studies help to delineate the role of domestic cats in disease transmission and response to variant emergence, establish a flexible translational model to develop strategies to prevent the spread of SARS-CoV-2, and identify potential targets for downstream therapeutic development.

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Platelet Phenotype Analysis of COVID-19 Patients Reveals Progressive Changes in the Activation of Integrin αIIbβ3, F13A1, the SARS-CoV-2 Target EIF4A1 and Annexin A5

Abstract: Graphical Abstract

Cited by 21 publications

References 73 publications

Signaling Through FcγRIIA and the C5a-C5aR Pathway Mediate Platelet Hyperactivation in COVID-19

Signaling Through FcγRIIA and the C5a-C5aR Pathway Mediate Platelet Hyperactivation in COVID-19

EMoMiS: A Pipeline for Epitope-based Molecular Mimicry Search in Protein Structures with Applications to SARS-CoV-2

SARS CoV-2 (Delta Variant) Infection Kinetics and Immunopathogenesis in Domestic Cats

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