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1.
Acta Neuropathol Commun ; 10(1): 14, 2022 02 01.
Article in English | MEDLINE | ID: covidwho-1690864

ABSTRACT

Coronavirus disease 2019 (COVID-19) is associated with an increased risk of thrombotic events. Ischemic stroke in COVID-19 patients entails high severity and mortality rates. Here we aimed to analyze cerebral thrombi of COVID-19 patients with large vessel occlusion (LVO) acute ischemic stroke to expose molecular evidence for SARS-CoV-2 in the thrombus and to unravel any peculiar immune-thrombotic features. We conducted a systematic pathological analysis of cerebral thrombi retrieved by endovascular thrombectomy in patients with LVO stroke infected with COVID-19 (n = 7 patients) and non-covid LVO controls (n = 23). In thrombi of COVID-19 patients, the SARS-CoV-2 docking receptor ACE2 was mainly expressed in monocytes/macrophages and showed higher expression levels compared to controls. Using polymerase chain reaction and sequencing, we detected SARS-CoV-2 Clade20A, in the thrombus of one COVID-19 patient. Comparing thrombus composition of COVID-19 and control patients, we noted no overt differences in terms of red blood cells, fibrin, neutrophil extracellular traps (NETs), von Willebrand Factor (vWF), platelets and complement complex C5b-9. However, thrombi of COVID-19 patients showed increased neutrophil density (MPO+ cells) and a three-fold higher Neutrophil-to-Lymphocyte Ratio (tNLR). In the ROC analysis both neutrophils and tNLR had a good discriminative ability to differentiate thrombi of COVID-19 patients from controls. In summary, cerebral thrombi of COVID-19 patients can harbor SARS-CoV2 and are characterized by an increased neutrophil number and tNLR and higher ACE2 expression. These findings suggest neutrophils as the possible culprit in COVID-19-related thrombosis.


Subject(s)
Brain Ischemia/immunology , COVID-19/immunology , Immunity, Cellular/physiology , Intracranial Thrombosis/immunology , Neutrophils/immunology , Stroke/immunology , Aged , Aged, 80 and over , Angiotensin-Converting Enzyme 2/blood , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/immunology , Brain Ischemia/blood , Brain Ischemia/genetics , COVID-19/blood , COVID-19/genetics , Female , Humans , Intracranial Thrombosis/blood , Intracranial Thrombosis/genetics , Male , Mechanical Thrombolysis/methods , Middle Aged , Neutrophils/metabolism , Prospective Studies , SARS-CoV-2/genetics , SARS-CoV-2/immunology , SARS-CoV-2/metabolism , Stroke/blood , Stroke/genetics
2.
PLoS Med ; 18(3): e1003553, 2021 03.
Article in English | MEDLINE | ID: covidwho-1117467

ABSTRACT

BACKGROUND: Epidemiological studies report associations of diverse cardiometabolic conditions including obesity with COVID-19 illness, but causality has not been established. We sought to evaluate the associations of 17 cardiometabolic traits with COVID-19 susceptibility and severity using 2-sample Mendelian randomization (MR) analyses. METHODS AND FINDINGS: We selected genetic variants associated with each exposure, including body mass index (BMI), at p < 5 × 10-8 from genome-wide association studies (GWASs). We then calculated inverse-variance-weighted averages of variant-specific estimates using summary statistics for susceptibility and severity from the COVID-19 Host Genetics Initiative GWAS meta-analyses of population-based cohorts and hospital registries comprising individuals with self-reported or genetically inferred European ancestry. Susceptibility was defined as testing positive for COVID-19 and severity was defined as hospitalization with COVID-19 versus population controls (anyone not a case in contributing cohorts). We repeated the analysis for BMI with effect estimates from the UK Biobank and performed pairwise multivariable MR to estimate the direct effects and indirect effects of BMI through obesity-related cardiometabolic diseases. Using p < 0.05/34 tests = 0.0015 to declare statistical significance, we found a nonsignificant association of genetically higher BMI with testing positive for COVID-19 (14,134 COVID-19 cases/1,284,876 controls, p = 0.002; UK Biobank: odds ratio 1.06 [95% CI 1.02, 1.10] per kg/m2; p = 0.004]) and a statistically significant association with higher risk of COVID-19 hospitalization (6,406 hospitalized COVID-19 cases/902,088 controls, p = 4.3 × 10-5; UK Biobank: odds ratio 1.14 [95% CI 1.07, 1.21] per kg/m2, p = 2.1 × 10-5). The implied direct effect of BMI was abolished upon conditioning on the effect on type 2 diabetes, coronary artery disease, stroke, and chronic kidney disease. No other cardiometabolic exposures tested were associated with a higher risk of poorer COVID-19 outcomes. Small study samples and weak genetic instruments could have limited the detection of modest associations, and pleiotropy may have biased effect estimates away from the null. CONCLUSIONS: In this study, we found genetic evidence to support higher BMI as a causal risk factor for COVID-19 susceptibility and severity. These results raise the possibility that obesity could amplify COVID-19 disease burden independently or through its cardiometabolic consequences and suggest that targeting obesity may be a strategy to reduce the risk of severe COVID-19 outcomes.


Subject(s)
Body Mass Index , COVID-19 , Coronary Artery Disease , Diabetes Mellitus, Type 2 , Disease Susceptibility , Obesity , Renal Insufficiency, Chronic , Stroke , COVID-19/diagnosis , COVID-19/epidemiology , COVID-19/genetics , Cardiometabolic Risk Factors , Causality , Coronary Artery Disease/epidemiology , Coronary Artery Disease/genetics , Diabetes Mellitus, Type 2/epidemiology , Diabetes Mellitus, Type 2/genetics , Genetic Variation , Genome-Wide Association Study/statistics & numerical data , Humans , Mendelian Randomization Analysis , Meta-Analysis as Topic , Obesity/diagnosis , Obesity/epidemiology , Obesity/metabolism , Renal Insufficiency, Chronic/epidemiology , Renal Insufficiency, Chronic/genetics , SARS-CoV-2 , Severity of Illness Index , Stroke/epidemiology , Stroke/genetics
4.
Platelets ; 32(3): 314-324, 2021 Apr 03.
Article in English | MEDLINE | ID: covidwho-748271

ABSTRACT

Platelets are increasingly being recognized for playing roles beyond thrombosis and hemostasis. Today we know that they mediate inflammation by direct interactions with innate immune cells or secretion of cytokines/chemokines. Here we review their interactions with neutrophils and monocytes/macrophages in infection and sepsis, stroke, myocardial infarction and venous thromboembolism. We discuss new roles for platelet surface receptors like GPVI or GPIb and also look at platelet contributions to the formation of neutrophil extracellular traps (NETs) as well as to deep vein thrombosis during infection, e.g. in COVID-19 patients.


Subject(s)
Blood Platelets/immunology , COVID-19/immunology , Myocardial Infarction/immunology , Neutrophils/immunology , Sepsis/immunology , Stroke/immunology , Venous Thromboembolism/immunology , Blood Platelets/pathology , COVID-19/genetics , COVID-19/pathology , COVID-19/virology , Cell Communication/genetics , Cell Communication/immunology , Cytokines/genetics , Cytokines/immunology , Extracellular Traps/genetics , Extracellular Traps/immunology , Gene Expression Regulation , Humans , Inflammation , Macrophages/immunology , Macrophages/pathology , Monocytes/immunology , Monocytes/pathology , Myocardial Infarction/genetics , Myocardial Infarction/pathology , Neutrophils/pathology , Platelet Glycoprotein GPIb-IX Complex/genetics , Platelet Glycoprotein GPIb-IX Complex/immunology , Platelet Membrane Glycoproteins/genetics , Platelet Membrane Glycoproteins/immunology , Sepsis/genetics , Sepsis/pathology , Stroke/genetics , Stroke/pathology , Venous Thromboembolism/genetics , Venous Thromboembolism/pathology
5.
J Neurovirol ; 26(5): 619-630, 2020 10.
Article in English | MEDLINE | ID: covidwho-728290

ABSTRACT

The recent pandemic outbreak of coronavirus is pathogenic and a highly transmittable viral infection caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2). In this time of ongoing pandemic, many emerging reports suggested that the SARS-CoV-2 has inimical effects on neurological functions, and even causes serious neurological damage. The neurological symptoms associated with COVID-19 include headache, dizziness, depression, anosmia, encephalitis, stroke, epileptic seizures, and Guillain-Barre syndrome along with many others. The involvement of the CNS may be related with poor prognosis and disease worsening. Here, we review the evidence of nervous system involvement and currently known neurological manifestations in COVID-19 infections caused by SARS-CoV-2. We prioritize the 332 human targets of SARS-CoV-2 according to their association with brain-related disease and identified 73 candidate genes. We prioritize these 73 genes according to their spatio-temporal expression in the different regions of brain and also through evolutionary intolerance analysis. The prioritized genes could be considered potential indicators of COVID-19-associated neurological symptoms and thus act as a possible therapeutic target for the prevention and treatment of CNS manifestations associated with COVID-19 patients.


Subject(s)
Betacoronavirus/pathogenicity , Brain/metabolism , Coronavirus Infections/genetics , Host-Pathogen Interactions/genetics , Nerve Tissue Proteins/genetics , Pneumonia, Viral/genetics , Viral Proteins/genetics , Brain/pathology , Brain/virology , COVID-19 , Coronavirus Infections/complications , Coronavirus Infections/pathology , Coronavirus Infections/virology , Depression , Dizziness/complications , Dizziness/genetics , Dizziness/pathology , Dizziness/virology , Encephalitis/complications , Encephalitis/genetics , Encephalitis/pathology , Encephalitis/virology , Guillain-Barre Syndrome/complications , Guillain-Barre Syndrome/genetics , Guillain-Barre Syndrome/pathology , Guillain-Barre Syndrome/virology , Headache/complications , Headache/genetics , Headache/pathology , Headache/virology , Humans , Nerve Tissue Proteins/classification , Nerve Tissue Proteins/metabolism , Olfaction Disorders/complications , Olfaction Disorders/genetics , Olfaction Disorders/pathology , Olfaction Disorders/virology , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Protein Interaction Mapping , SARS-CoV-2 , Seizures/complications , Seizures/genetics , Seizures/pathology , Seizures/virology , Severity of Illness Index , Stroke/complications , Stroke/genetics , Stroke/pathology , Stroke/virology , Viral Proteins/metabolism
6.
Biochem Biophys Res Commun ; 528(3): 413-419, 2020 07 30.
Article in English | MEDLINE | ID: covidwho-436643

ABSTRACT

Coronavirus disease 2019 (COVID-19) is a worldwide pandemic. It has a high transmission rate among humans, and is a threat to global public health. However, there are no effective prophylactics or therapeutics available. It is necessary to identify vulnerable and susceptible groups for adequate protection and care against this disease. Recent studies have reported that COVID-19 has angiotensin-converting enzyme 2 (ACE2) as a functional receptor, which may lead to the development of severe cerebrovascular diseases (CVD), including strokes, in patients with risk factors for CVD such as diabetes and smoking. Thus, the World Health Organization (WHO) advised caution against COVID-19 for smokers and patients with underlying clinical symptoms, including cardiovascular diseases. Here, we observed ACE2 expression in the brain of rat middle cerebral artery occlusion (MCAO) model and evaluated the effects of cigarette smoke extract (CSE) and diabetes on ACE2 expression in vessels. We showed that the levels of ACE2 expression was increased in the cortex penumbra after ischemic injuries. CSE treatment significantly elevated ACE2 expression in human brain vessels. We found that ACE2 expression was upregulated in primary cultured human blood vessels with diabetes compared to healthy controls. This study demonstrates that ACE2 expression is increased in ischemic brains and vessels exposed to diabetes or smoking, makes them vulnerable to COVID-19 infection.


Subject(s)
Betacoronavirus/metabolism , Brain Ischemia/virology , Brain/blood supply , Diabetes Mellitus , Peptidyl-Dipeptidase A/biosynthesis , Receptors, Virus/biosynthesis , Smokers , Stroke/virology , Up-Regulation , Angiotensin-Converting Enzyme 2 , Animals , Betacoronavirus/pathogenicity , Brain/drug effects , Brain Ischemia/genetics , Brain Ischemia/metabolism , COVID-19 , Coronavirus Infections/genetics , Coronavirus Infections/metabolism , Coronavirus Infections/virology , Diabetes Mellitus/genetics , Diabetes Mellitus/metabolism , Disease Models, Animal , Disease Susceptibility , Infarction, Middle Cerebral Artery/complications , Male , Mice , Mice, Inbred C57BL , Pandemics , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/genetics , Pneumonia, Viral/metabolism , Pneumonia, Viral/virology , Rats , Rats, Sprague-Dawley , Receptors, Virus/genetics , SARS-CoV-2 , Smoke/adverse effects , Stroke/genetics , Stroke/metabolism , Up-Regulation/drug effects
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