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1.
Front Immunol ; 13: 879157, 2022.
Article in English | MEDLINE | ID: covidwho-1933664

ABSTRACT

During the COVID-19 pandemic, vaccination is the most important countermeasure. Pharmacovigilance concerns however emerged with very rare, but potentially disastrous thrombotic complications following vaccination with ChAdOx1. Platelet factor-4 antibody mediated vaccine-induced immune thrombotic thrombocytopenia (VITT) was described as an underlying mechanism of these thrombotic events. Recent work moreover suggests that mechanisms of immunothrombosis including neutrophil extracellular trap (NET) formation might be critical for thrombogenesis during VITT. In this study, we investigated blood and thrombus specimens of a female patient who suffered severe stroke due to VITT after vaccination with ChAdOx1 in comparison to 13 control stroke patients with similar clinical characteristics. We analyzed cerebral thrombi using histological examination, staining of complement factors, NET-markers, DNase and LL-37. In blood samples at the hyper-acute phase of stroke and 7 days later, we determined cell-free DNA, myeloperoxidase-histone complexes, DNase activity, myeloperoxidase activity, LL-37 and inflammatory cytokines. NET markers were identified in thrombi of all patients. Interestingly, the thrombus of the VITT-patient exclusively revealed complement factors and high amounts of DNase and LL-37. High DNase activity was also measured in blood, implying a disturbed NET-regulation. Furthermore, serum of the VITT-patient inhibited reactive oxygen species-dependent NET-release by phorbol-myristate-acetate to a lesser degree compared to controls, indicating either less efficient NET-inhibition or enhanced NET-induction in the blood of the VITT-patient. Additionally, the changes in specific cytokines over time were emphasized in the VITT-patient as well. In conclusion, insufficient resolution of NETs, e.g. by endogenous DNases or protection of NETs against degradation by embedded factors like the antimicrobial peptide LL-37 might thus be an important factor in the pathology of VITT besides increased NET-formation. On the basis of these findings, we discuss the potential implications of the mechanisms of disturbed NETs-degradation for diagnostic and therapeutic approaches in VITT-related thrombogenesis, other auto-immune disorders and beyond.


Subject(s)
COVID-19 , Extracellular Traps , Purpura, Thrombocytopenic, Idiopathic , Stroke , Thrombocytopenia , Thrombosis , Vaccines , Deoxyribonuclease I/metabolism , Deoxyribonucleases , Female , Humans , Neutrophils , Pandemics , Peroxidase/metabolism , Platelet Factor 4/metabolism , Purpura, Thrombocytopenic, Idiopathic/metabolism , Stroke/etiology , Stroke/metabolism , Thrombocytopenia/chemically induced , Thrombocytopenia/metabolism , Thrombosis/etiology , Thrombosis/metabolism , Vaccines/metabolism
2.
Vet Pathol ; 59(4): 661-672, 2022 07.
Article in English | MEDLINE | ID: covidwho-1613175

ABSTRACT

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), resulted in an ongoing pandemic with millions of deaths worldwide. Infection of humans can be asymptomatic or result in fever, fatigue, dry cough, dyspnea, and acute respiratory distress syndrome with multiorgan failure in severe cases. The pathogenesis of COVID-19 is not fully understood, and various models employing different species are currently applied. Ferrets can be infected with SARS-CoV-2 and efficiently transmit the virus to contact animals. In contrast to hamsters, ferrets usually show mild disease and viral replication restricted to the upper airways. Most reports have used the intranasal inoculation route, while the intratracheal infection model is not well characterized. Herein, we present clinical, virological, and pathological data from young ferrets intratracheally inoculated with SARS-CoV-2. Infected animals showed no significant clinical signs, and had transient infection with peak viral RNA loads at 4 days postinfection, mild to moderate rhinitis, and pulmonary endothelialitis/vasculitis. Viral antigen was exclusively found in the respiratory epithelium of the nasal cavity, indicating a particular tropism for cells in this location. Viral antigen was associated with epithelial damage and influx of inflammatory cells, including activated neutrophils releasing neutrophil extracellular traps. Scanning electron microscopy of the nasal respiratory mucosa revealed loss of cilia, shedding, and rupture of epithelial cells. The currently established ferret SARS-CoV-2 infection models are comparatively discussed with SARS-CoV-2 pathogenesis in mink, and the advantages and disadvantages of both species as research models for zoonotic betacoronaviruses are highlighted.


Subject(s)
COVID-19 , Rodent Diseases , Animals , Antigens, Viral , COVID-19/veterinary , Cricetinae , Disease Models, Animal , Ferrets , Respiratory Mucosa , SARS-CoV-2
3.
Front Immunol ; 12: 640842, 2021.
Article in English | MEDLINE | ID: covidwho-1207697

ABSTRACT

Neutrophil extracellular traps (NETs) have been identified as one pathogenetic trigger in severe COVID-19 cases and therefore well-described animal models to understand the influence of NETs in COVID-19 pathogenesis are needed. SARS-CoV-2 infection causes infection and interstitial pneumonia of varying severity in humans and COVID-19 models. Pulmonary as well as peripheral vascular lesions represent a severe, sometimes fatal, disease complication of unknown pathogenesis in COVID-19 patients. Furthermore, neutrophil extracellular traps (NETs), which are known to contribute to vessel inflammation or endothelial damage, have also been shown as potential driver of COVID-19 in humans. Though most studies in animal models describe the pulmonary lesions characterized by interstitial inflammation, type II pneumocyte hyperplasia, edema, fibrin formation and infiltration of macrophages and neutrophils, detailed pathological description of vascular lesions or NETs in COVID-19 animal models are lacking so far. Here we report different types of pulmonary vascular lesions in the golden Syrian hamster model of COVID-19. Vascular lesions included endothelialitis and vasculitis at 3 and 6 days post infection (dpi), and were almost nearly resolved at 14 dpi. Importantly, virus antigen was present in pulmonary lesions, but lacking in vascular alterations. In good correlation to these data, NETs were detected in the lungs of infected animals at 3 and 6 dpi. Hence, the Syrian hamster seems to represent a useful model to further investigate the role of vascular lesions and NETs in COVID-19 pathogenesis.


Subject(s)
COVID-19/pathology , Disease Models, Animal , Extracellular Traps/immunology , Lung/pathology , SARS-CoV-2/pathogenicity , Vasculitis/pathology , Animals , COVID-19/immunology , COVID-19/virology , Cricetinae , Lung/immunology , Lung/virology , Mesocricetus , Vasculitis/immunology , Viral Proteins/metabolism
4.
mBio ; 12(1)2021 02 16.
Article in English | MEDLINE | ID: covidwho-1088202

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is leading to public health crises worldwide. An understanding of the pathogenesis and the development of treatment strategies is of high interest. Recently, neutrophil extracellular traps (NETs) have been identified as a potential driver of severe SARS-CoV-2 infections in humans. NETs are extracellular DNA fibers released by neutrophils after contact with various stimuli and accumulate antimicrobial substances or host defense peptides. When massively released, NETs are described to contribute to immunothrombosis in acute respiratory distress syndrome and in vascular occlusions. Based on the increasing evidence that NETs contribute to severe COVID-19 cases, DNase treatment of COVID-19 patients to degrade NETs is widely discussed as a potential therapeutic strategy. Here, we discuss potential detrimental effects of NETs and their nuclease degradation, since NET fragments can boost certain bacterial coinfections and thereby increase the severity of the disease.


Subject(s)
COVID-19/metabolism , Coinfection/metabolism , Extracellular Traps/metabolism , Neutrophils/metabolism , Bacterial Infections/metabolism , Coinfection/microbiology , Coinfection/virology , Humans
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