Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 20 de 341
Filter
1.
Rinsho Ketsueki ; 63(5): 403-409, 2022.
Article in Japanese | MEDLINE | ID: covidwho-1879647

ABSTRACT

The mortality rate due to coronavirus disease 2019 (COVID-19) reached 5.3 million. However, identifying the novel treatment targets that ultimately reduce or prevent disease aggravation will be possible by understanding the mechanism and pathophysiology underlying the COVID-19 aggravation. Authors of previous studies have identified the "cytokine storm" that constitutes the secretion of inflammatory cytokines driven by the coagulation/fibrinolytic system as an inflammatory cytodynamic control mechanism that contributes to the aggravated COVID-19 pathology and the pathophysiology of related diseases. Vasculature-lining endothelial cells are bioreactors that produce or contribute to the modulation status of cytokines and coagulation and fibrinolytic system factors. The key steps in the pathophysiology of organ damage include the destabilization of the angiocrine system triggered by vascular endothelial damage during severe COVID-19. Overproduced or imbalanced angiocrine factors and inflammatory cytokines contribute to major COVID-19 complications. Within its scope, this study outlines the significance of the fibrinolytic system in the pathophysiology of inflammatory diseases, focusing on the research results. The possibility of molecular that target these angiocrine and fibrinolytic factors for inflammatory diseases as novel treatment approaches for inflammatory diseases, such as COVID-19, was discussed.


Subject(s)
COVID-19 , Cytokine Release Syndrome , COVID-19/drug therapy , Cytokine Release Syndrome/drug therapy , Cytokines , Endothelial Cells , Humans , SARS-CoV-2
2.
Fluids Barriers CNS ; 19(1): 46, 2022 Jun 07.
Article in English | MEDLINE | ID: covidwho-1879246

ABSTRACT

BACKGROUND: Knowledge of the entry receptors responsible for SARS-CoV-2 is key to understand the neural transmission and pathogenesis of COVID-19 characterized by a neuroinflammatory scenario. Understanding the brain distribution of angiotensin converting enzyme 2 (ACE2), the primary entry receptor for SARS-CoV-2, remains mixed. Smoking has been shown as a risk factor for COVID-19 severity and it is not clear how smoking exacerbates the neural pathogenesis in smokers. METHODS: Immunohistochemistry, real-time PCR and western blot assays were used to systemically examine the spatial-, cell type- and isoform-specific expression of ACE2 in mouse brain and primary cultured brain cells. Experimental smoking exposure was conducted to evaluate the effect of smoking on brain expression. RESULTS: We observed ubiquitous expression of ACE2 but uneven brain distribution, with high expression in the cerebral microvasculature, medulla oblongata, hypothalamus, subventricular zones, and meninges around medulla oblongata and hypothalamus. Co-staining with cell type-specific markers demonstrates ACE2 is primarily expressed in astrocytes around the microvasculature, medulla oblongata, hypothalamus, ventricular and subventricular zones of cerebral ventricles, and subependymal zones in rhinoceles and rostral migratory streams, radial glial cells in the lateral ventricular zones, tanycytes in the third ventricle, epithelial cells and stroma in the cerebral choroid plexus, as well as cerebral pericytes, but rarely detected in neurons and cerebral endothelial cells. ACE2 expression in astrocytes is further confirmed in primary cultured cells. Furthermore, isoform-specific analysis shows astrocyte ACE2 has the peptidase domain responsible for SARS-CoV-2 entry, indicating astrocytes are indeed vulnerable to SARS-CoV-2 infection. Finally, our data show experimental tobacco smoking and electronic nicotine vaping exposure increase proinflammatory and/or immunomodulatory cytokine IL-1a, IL-6 and IL-5 without significantly affecting ACE2 expression in the brain, suggesting smoking may pre-condition a neuroinflammatory state in the brain. CONCLUSIONS: The present study demonstrates a spatial- and cell type-specific expression of ACE2 in the brain, which might help to understand the acute and lasting post-infection neuropsychological manifestations in COVID-19 patients. Our data highlights a potential role of astrocyte ACE2 in the neural transmission and pathogenesis of COVID-19. This also suggests a pre-conditioned neuroinflammatory and immunocompromised scenario might attribute to exacerbated COVID-19 severity in the smokers.


Subject(s)
COVID-19 , Vaping , Angiotensin-Converting Enzyme 2 , Animals , Astrocytes , Endothelial Cells , Humans , Mice , SARS-CoV-2 , Smoking/adverse effects , Synaptic Transmission , Tobacco Smoking
3.
Int J Mol Sci ; 23(11)2022 May 31.
Article in English | MEDLINE | ID: covidwho-1869643

ABSTRACT

The endothelium has a fundamental role in the cardiovascular complications of coronavirus disease 2019 (COVID-19). Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) particularly affects endothelial cells. The virus binds to the angiotensin-converting enzyme 2 (ACE-2) receptor (present on type 2 alveolar cells, bronchial epithelial cells, and endothelial cells), and induces a cytokine storm. The cytokines tumor necrosis factor alpha, interleukin-1 beta, and interleukin-6 have particular effects on endothelial cells-leading to endothelial dysfunction, endothelial cell death, changes in tight junctions, and vascular hyperpermeability. Under normal conditions, apoptotic endothelial cells are removed into the bloodstream. During COVID-19, however, endothelial cells are detached more rapidly, and do not regenerate as effectively as usual. The loss of the endothelium on the luminal surface abolishes all of the vascular responses mediated by the endothelium and nitric oxide production in particular, which results in greater contractility. Moreover, circulating endothelial cells infected with SARS-CoV-2 act as vectors for viral dissemination by forming clusters that migrate into the circulation and reach distant organs. The cell clusters and the endothelial dysfunction might contribute to the various thromboembolic pathologies observed in COVID-19 by inducing the formation of intravascular microthrombi, as well as by triggering disseminated intravascular coagulation. Here, we review the contributions of endotheliopathy and endothelial-cell-derived extracellular vesicles to the pathogenesis of COVID-19, and discuss therapeutic strategies that target the endothelium in patients with COVID-19.


Subject(s)
COVID-19 , Vascular Diseases , COVID-19/complications , Cytokines/metabolism , Endothelial Cells/metabolism , Endothelium, Vascular/metabolism , Humans , SARS-CoV-2 , Vascular Diseases/metabolism
4.
Cells ; 11(10)2022 May 20.
Article in English | MEDLINE | ID: covidwho-1869480

ABSTRACT

Successful neuroprotection is only possible with contemporary microvascular protection. The prevention of disease-induced vascular modifications that accelerate brain damage remains largely elusive. An improved understanding of pericyte (PC) signalling could provide important insight into the function of the neurovascular unit (NVU), and into the injury-provoked responses that modify cell-cell interactions and crosstalk. Due to sharing the same basement membrane with endothelial cells, PCs have a crucial role in the control of endothelial, astrocyte, and oligodendrocyte precursor functions and hence blood-brain barrier stability. Both cerebrovascular and neurodegenerative diseases impair oxygen delivery and functionally impair the NVU. In this review, the role of PCs in central nervous system health and disease is discussed, considering their origin, multipotency, functions and also dysfunction, focusing on new possible avenues to modulate neuroprotection. Dysfunctional PC signalling could also be considered as a potential biomarker of NVU pathology, allowing us to individualize therapeutic interventions, monitor responses, or predict outcomes.


Subject(s)
Endothelial Cells , Pericytes , Astrocytes , Blood-Brain Barrier/pathology , Cell Communication , Endothelial Cells/physiology , Pericytes/pathology
5.
PLoS One ; 17(5): e0268296, 2022.
Article in English | MEDLINE | ID: covidwho-1855026

ABSTRACT

Severe coronavirus disease-19 (COVID-19) is characterized by vascular inflammation and thrombosis. We and others have proposed that the inflammatory response to coronavirus infection activates endothelial cells, leading to endothelial release of pro-thrombotic proteins. These mediators can trigger obstruction of the pulmonary microvasculature, leading to worsening oxygenation, acute respiratory distress syndrome, and death. In the current study, we tested the hypothesis that higher levels of biomarkers released from endothelial cells are associated with worse oxygenation in patients with COVID-19. We studied 83 participants aged 18-84 years with COVID-19 admitted to a single center. The severity of pulmonary disease was classified by oxygen requirement, including no oxygen requirement, low-flow oxygen, high-flow nasal cannula oxygen, mechanical ventilation, and death. We measured plasma levels of two proteins released by activated endothelial cells, von Willebrand Factor (VWF) antigen and soluble P-Selectin (sP-Sel), and a biomarker of systemic thrombosis, D-dimer. Additionally, we explored the association of endothelial biomarker levels with the levels of pro-inflammatory cytokine and chemokines, and vascular inflammation biomarkers. We found that levels of VWF, sP-sel, and D-dimer were increased in individuals with more severe COVID-19 pulmonary disease. Biomarkers of endothelial cell activation were also correlated with proinflammatory cytokines and chemokines. Taken together, our data demonstrate increased levels of VWF and sP-selectin are linked to the severity of lung disease in COVID-19 and correlated with biomarkers of inflammation and vascular inflammation. Our data support the concept that COVID-19 is a vascular disease which involves endothelial injury in the context of an inflammatory state.


Subject(s)
COVID-19 , Thrombosis , Biomarkers , Chemokines/metabolism , Endothelial Cells/metabolism , Endothelium, Vascular/metabolism , Humans , Inflammation/metabolism , Oxygen/metabolism , Thrombosis/metabolism , von Willebrand Factor/metabolism
8.
Eur Rev Med Pharmacol Sci ; 26(8): 3025-3029, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1836395

ABSTRACT

OBJECTIVE: Previous studies have confirmed the key mechanism by which SARS-CoV-2 enters human cells. It is well established that ACE2 is the receptor that can mark the beginning of the infection. In light of this, the organs that express higher levels of ACE2 are generally considered at higher risk, while those with lower levels should be somehow more protected. This - if related to the scarcity of ace2-expressing cells in the brain - seems to contrast with the presence of a variety of neurological symptoms that follow infection with ace2.  The aim of this work was to analyze ACE2 expression in the human brain, focusing on the choroid plexuses. PATIENTS AND METHODS: Twenty brain samples were obtained at autopsy from ten human fetuses and from ten adult subjects. All samples were selected to contain the choroid plexus. Specimens were fixed in 10% formalin, routinely processed and paraffin embedded. 5-micron sections were stained with Hematoxylin and Eosin (H&E) and immunostained with a commercial anti-human ACE2 rabbit monoclonal antibody at 1:100 dilution. RESULTS: We analyzed 20 samples by immunohistochemistry, and we noted that, as far as fetal samples are concerned, a strong reactivity for ACE2 was detected in the myxoid stroma of the choroid plexuses and in the endothelial cells in fetuses. The complete absence of the ACE2 marker was detected in epithelial cells, neurons and glial cells of the cerebral cortex, both in fetuses and in adults. Whereas a  strong but selective reactivity for ACE2 was also detected in adult choroid plexuses, mainly localized in the endothelial cells of the choroid capillaries. CONCLUSIONS: Our study shows a strong expression of ACE in the fetal and adult brain choroid plexuses. This new histopathological finding may clarify the susceptibility of the human brain to SARS-COV-2 infection. Our data indicate the choroid plexus as the entry gate of virus for in the human brain; therefore, the entrance of SARS-CoV-2 into the cerebrospinal fluid through the choroid plexuses might represent the mechanism utilized by this coronavirus to cause direct injury to brain cells.


Subject(s)
Angiotensin-Converting Enzyme 2 , COVID-19 , Choroid , Choroid Plexus , Endothelial Cells , Humans , SARS-CoV-2
9.
Zool Res ; 43(3): 457-468, 2022 May 18.
Article in English | MEDLINE | ID: covidwho-1836354

ABSTRACT

COVID-19 is an immune-mediated inflammatory disease caused by SARS-CoV-2 infection, the combination of anti-inflammatory and antiviral therapy is predicted to provide clinical benefits. We recently demonstrated that mast cells (MCs) are an essential mediator of SARS-CoV-2-initiated hyperinflammation. We also showed that spike protein-induced MC degranulation initiates alveolar epithelial inflammation for barrier disruption and suggested an off-label use of antihistamines as MC stabilizers to block degranulation and consequently suppress inflammation and prevent lung injury. In this study, we emphasized the essential role of MCs in SARS-CoV-2-induced lung lesions in vivo, and demonstrated the benefits of co-administration of antihistamines and antiviral drug remdesivir in SARS-CoV-2-infected mice. Specifically, SARS-CoV-2 spike protein-induced MC degranulation resulted in alveolar-capillary injury, while pretreatment of pulmonary microvascular endothelial cells with antihistamines prevented adhesion junction disruption; predictably, the combination of antiviral drug remdesivir with the antihistamine loratadine, a histamine receptor 1 (HR1) antagonist, dampened viral replication and inflammation, thereby greatly reducing lung injury. Our findings emphasize the crucial role of MCs in SARS-CoV-2-induced inflammation and lung injury and provide a feasible combination antiviral and anti-inflammatory therapy for COVID-19 treatment.


Subject(s)
COVID-19 , Lung Injury , Rodent Diseases , Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Animals , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/drug therapy , COVID-19/veterinary , Endothelial Cells , Histamine Antagonists/therapeutic use , Inflammation/drug therapy , Inflammation/etiology , Inflammation/veterinary , Lung Injury/drug therapy , Lung Injury/veterinary , Mice , Rodent Diseases/drug therapy , SARS-CoV-2 , Spike Glycoprotein, Coronavirus
10.
Med Sci Monit ; 28: e937048, 2022 May 01.
Article in English | MEDLINE | ID: covidwho-1835855

ABSTRACT

The consequences of SARS-CoV-2 infection include short-term, long-term, mild, and severe clinical symptoms. The cardiovascular system, including endothelial cells, vascular smooth muscle cells, and cardiac myocytes, are important targets for SARS-CoV-2. In February 2022, the findings from a large US cohort of individuals diagnosed with COVID-19 and two sets of control cohorts evaluated the risk and 12-month cardiovascular disease burden. Individuals who had COVID-19 had a 72% increased risk of heart failure, a 63% increased risk of myocardial infarction, and a 52% increased risk of ischemic stroke compared with controls. These results were independent of gender, race, age, and other cardiovascular risk factors, including diabetes, obesity, hypertension, hyperlipidemia, and chronic kidney disease. As of 25 April 2022, the World Health Organization (WHO) reported that more than 80 million people in the US, more than 22 million people in the UK, and more than 505 million people worldwide were infected with SARS-CoV-2. This Editorial aims to present what is currently known about the cardiovascular outcomes at one year following SARS-CoV-2 infection and highlights that primary care physicians should be mindful of the COVID-19 infection status of their patients when evaluating cardiovascular health.


Subject(s)
COVID-19 , Cardiovascular Diseases , COVID-19/complications , Cardiovascular Diseases/etiology , Endothelial Cells , Heart Disease Risk Factors , Humans , Risk Factors , SARS-CoV-2
11.
JCI Insight ; 7(11)2022 Jun 08.
Article in English | MEDLINE | ID: covidwho-1832829

ABSTRACT

Studies have demonstrated the phenotypic heterogeneity of vascular endothelial cells (ECs) within a vascular bed; however, little is known about how distinct endothelial subpopulations in a particular organ respond to an inflammatory stimulus. We performed single-cell RNA-Seq of 35,973 lung ECs obtained during baseline as well as postinjury time points after inflammatory lung injury induced by LPS. Seurat clustering and gene expression pathway analysis identified 2 major subpopulations in the lung microvascular endothelium, a subpopulation enriched for expression of immune response genes such as MHC genes (immuneEC) and another defined by increased expression of vascular development genes such as Sox17 (devEC). The presence of immuneEC and devEC subpopulations was also observed in nonhuman primate lungs infected with SARS-CoV-2 and murine lungs infected with H1N1 influenza virus. After the peak of inflammatory injury, we observed the emergence of a proliferative lung EC subpopulation. Overexpression of Sox17 prevented inflammatory activation in ECs. Thus, there appeared to be a "division of labor" within the lung microvascular endothelium in which some ECs showed propensity for inflammatory signaling and others for endothelial regeneration. These results provide underpinnings for the development of targeted therapies to limit inflammatory lung injury and promote regeneration.


Subject(s)
COVID-19 , Influenza A Virus, H1N1 Subtype , Lung Injury , Animals , Endothelial Cells/metabolism , Lung/metabolism , Lung Injury/metabolism , Mice , SARS-CoV-2 , Transcriptome
12.
Mech Ageing Dev ; 204: 111667, 2022 Jun.
Article in English | MEDLINE | ID: covidwho-1829159

ABSTRACT

The COVID-19 pandemic caused by SARS-CoV-2 infection has been of unprecedented clinical and socio-economic worldwide relevance. The case fatality rate for COVID-19 grows exponentially with age and the presence of comorbidities. In the older patients, COVID-19 manifests predominantly as a systemic disease associated with immunological, inflammatory, and procoagulant responses. Timely diagnosis and risk stratification are crucial steps to define appropriate therapies and reduce mortality, especially in the older patients. Chronically and systemically activated innate immune responses and impaired antiviral responses have been recognized as the results of a progressive remodeling of the immune system during aging, which can be described by the words 'immunosenescence' and 'inflammaging'. These age-related features of the immune system were highlighted in patients affected by COVID-19 with the poorest clinical outcomes, suggesting that the mechanisms underpinning immunosenescence and inflammaging could be relevant for COVID-19 pathogenesis and progression. Increasing evidence suggests that senescent myeloid and endothelial cells are characterized by the acquisition of a senescence-associated pro-inflammatory phenotype (SASP), which is considered as the main culprit of both immunosenescence and inflammaging. Here, we reviewed this evidence and highlighted several circulating biomarkers of inflammaging that could provide additional prognostic information to stratify COVID-19 patients based on the risk of severe outcomes.


Subject(s)
COVID-19 , Aging , Biomarkers , COVID-19/diagnosis , Endothelial Cells , Humans , Inflammation , Pandemics , SARS-CoV-2
13.
BMC Nephrol ; 23(1): 176, 2022 05 06.
Article in English | MEDLINE | ID: covidwho-1822174

ABSTRACT

BACKGROUND: The coronavirus disease (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) produced a pandemic since March 2020 by affecting more than 243 million people with more than 5 million deaths globally. SARS-CoV-2 infection is produced by binding to angiotensin-converting enzyme, which among other sites is highly expressed in the endothelial cells of the blood vessels, pericytes and the heart, as well as in renal podocytes and proximal tubular epithelial cells. SARS-CoV-2 and cardiovascular disease (CVD) are interconnected by risk factors association with an increased incidence of the disease and by determining de novo cardiac complications. At the same time, COVID-19 disease can lead to acute kidney injury directly, or due to sepsis, multi-organ failure and shock. Therefore, the pre-existence of both CVD and chronic kidney disease (CKD) is linked with a higher risk of severe disease and worse prognosis. METHODS: The main aim of this study is to assess the CV risk in a CKD (stage 3 to 5), dialysis and kidney transplanted population, following SARS-CoV-2 infection, with focus on the endothelial dysfunction as compared to a control group of matched patients. By using clinical evaluation, flow-mediated dilatation, carotid-femoral pulse wave velocity, intima-media thickness, echocardiographic parameters, lung ultrasound, bioimpedance spectroscopy and a series of novel biomarkers, the investigators will determine the long-term impact of this disease on CV and renal outcomes. DISCUSSION: This study will address the challenges and implications in long-term CV sequeale of COVID-19 and focus on a better understanding of the underlying mechanisms and possible therapeutic options. TRIAL REGISTRATION: Patient enrolment in the trial started in January 2021 and is expected to finish at the end of 2022. The study can be found on ClinicalTrials.gov database with NCT05125913 identifier. Registered on 18 November 2021 - Retrospectively registered.


Subject(s)
COVID-19 , Cardiovascular Diseases , Renal Insufficiency, Chronic , COVID-19/epidemiology , Cardiovascular Diseases/epidemiology , Carotid Intima-Media Thickness , Controlled Clinical Trials as Topic , Endothelial Cells , Female , Humans , Kidney , Male , Multicenter Studies as Topic , Observational Studies as Topic , Pulse Wave Analysis , Renal Insufficiency, Chronic/epidemiology , Risk Assessment , SARS-CoV-2
14.
Medicine (Baltimore) ; 101(15): e29164, 2022 Apr 15.
Article in English | MEDLINE | ID: covidwho-1816324

ABSTRACT

ABSTRACT: Coronavirus disease 2019, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread worldwide, resulting in over 250 million infections and >5 million deaths. Most antiviral drugs and vaccines have shown limited efficacy against SARS-CoV-2. Clinical data revealed that except for the large number of self-healing mild cases, moderate and severe cases mostly survived after supportive treatment but not specific drug administration or vaccination. The endothelial system is the first physiological barrier, and its structural stability is of critical importance in conferring disease resistance. Membrane lipid components, particularly sphingosine-1-phosphate (S1P), play a central role in stabilizing the cell membrane.Here, we used "Boolean Operators" such as AND, OR, and NOT, to search for relevant research articles in PubMed, then reviewed the potential of S1P in inhibiting SARS-CoV-2 infection by stabilizing the endothelial system, this is the major aim of this review work.Reportedly, vasculitis and systemic inflammatory vascular diseases are caused by endothelial damage resulting from SARS-CoV-2 infection. S1P, S1P receptor (SIPR), and signaling were involved in the process of SARS-CoV-2 infection, and S1P potentially regulated the function of EC barrier, in turn, inhibited the SARS-CoV-2 to infect the endothelial cells, and ultimately has the promising therapeutic value to coronavirus disease 2019.Taken together, we conclude that maintaining or administering a high level of S1P will preserve the integrity of the EC structure and function, in turn, lowering the risk of SARS-CoV-2 infection and reducing complications and mortality.


Subject(s)
COVID-19 , Endothelial Cells , Humans , Lysophospholipids , SARS-CoV-2 , Sphingosine/analogs & derivatives
15.
Viruses ; 14(5)2022 Apr 25.
Article in English | MEDLINE | ID: covidwho-1810326

ABSTRACT

The vascular barrier is heavily injured following SARS-CoV-2 infection and contributes enormously to life-threatening complications in COVID-19. This endothelial dysfunction is associated with the phlogistic phenomenon of cytokine storms, thrombotic complications, abnormal coagulation, hypoxemia, and multiple organ failure. The mechanisms surrounding COVID-19 associated endotheliitis have been widely attributed to ACE2-mediated pathways. However, integrins are emerging as possible receptor candidates for SARS-CoV-2, and their complex intracellular signaling events are essential for maintaining endothelial homeostasis. Here, we showed that the spike protein of SARS-CoV-2 depends on its RGD motif to drive barrier dysregulation by hijacking integrin αVß3, expressed on human endothelial cells. This triggers the redistribution and internalization of major junction protein VE-Cadherin which leads to the barrier disruption phenotype. Both extracellular and intracellular inhibitors of integrin αVß3 prevented these effects, similarly to the RGD-cyclic peptide compound Cilengitide, which suggests that the spike protein-through its RGD motif-binds to αVß3 and elicits vascular leakage events. These findings support integrins as an additional receptor for SARS-CoV-2, particularly as integrin engagement can elucidate many of the adverse endothelial dysfunction events that stem from COVID-19.


Subject(s)
COVID-19 , Spike Glycoprotein, Coronavirus , Cadherins , Endothelial Cells/metabolism , Humans , Integrin alphaVbeta3 , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/metabolism
16.
Front Immunol ; 13: 876555, 2022.
Article in English | MEDLINE | ID: covidwho-1809408

ABSTRACT

SARS-CoV-2 infects cells via binding to ACE2 and TMPRSS2, which allows the virus to fuse with host cells. The viral RNA is detected in the placenta of SARS-CoV-2-infected pregnant women and infection is associated with adverse pregnancy complications. Therefore, we hypothesize that SARS-CoV-2 infection of placental cells induces pro-inflammatory cytokine release to contribute to placental dysfunction and impaired pregnancy outcomes. First, expression of ACE2 and TMPRSS2 was measured by qPCR in human primary cultured term cytotrophoblasts (CTBs), syncytiotrophoblast (STBs), term and first trimester decidual cells (TDCs and FTDCs, respectively), endometrial stromal cells (HESCs) as well as trophoblast cell lines HTR8, JEG3, placental microvascular endothelial cells (PMVECs) and endometrial endothelial cells (HEECs). Later, cultured HTR8, JEG3, PMVECs and HEECs were treated with 10, 100, 1000 ng/ml of recombinant (rh-) SARS-CoV-2 S-protein ± 10 ng/ml rh-IFNγ. Pro-inflammatory cytokines IL-1ß, 6 and 8, chemokines CCL2, CCL5, CXCL9 and CXCL10 as well as tissue factor (F3), the primary initiator of the extrinsic coagulation cascade, were measured by qPCR as well as secreted IL-6 and IL-8 levels were measured by ELISA. Immunohistochemical staining for SARS-CoV-2 spike protein was performed in placental specimens from SARS-CoV-2-positive and normal pregnancies. ACE2 levels were significantly higher in CTBs and STBs vs. TDCs, FTDCs and HESCs, while TMPRSS2 levels were not detected in TDCs, FTDCs and HESCs. HTR8 and JEG3 express ACE2 and TMPRSS2, while PMVECs and HEECs express only ACE2, but not TMPRSS2. rh-S-protein increased proinflammatory cytokines and chemokines levels in both trophoblast and endothelial cells, whereas rh-S-protein only elevated F3 levels in endothelial cells. rh-IFNγ ± rh-S-protein augments expression of cytokines and chemokines in trophoblast and endothelial cells. Elevated F3 expression by rh-IFNγ ± S-protein was observed only in PMVECs. In placental specimens from SARS-CoV-2-infected mothers, endothelial cells displayed higher immunoreactivity against spike protein. These findings indicated that SARS-CoV-2 infection in placental cells: 1) induces pro-inflammatory cytokine and chemokine release, which may contribute to the cytokine storm observed in severely infected pregnant women and related placental dysfunction; and 2) elevates F3 expression that may trigger systemic or placental thrombosis.


Subject(s)
COVID-19 , Placenta Diseases , Pregnancy Complications, Infectious , Angiotensin-Converting Enzyme 2 , Cell Line, Tumor , Cytokines/metabolism , Endothelial Cells/pathology , Female , Humans , Placenta/metabolism , Placenta Diseases/pathology , Pregnancy , Pregnant Women , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/metabolism , Thromboplastin/metabolism
17.
JCI Insight ; 7(11)2022 Jun 08.
Article in English | MEDLINE | ID: covidwho-1807764

ABSTRACT

COVID-19 infection causes collapse of glomerular capillaries and loss of podocytes, culminating in a severe kidney disease called COVID-19-associated nephropathy (COVAN). The underlying mechanism of COVAN is unknown. We hypothesized that cytokines induced by COVID-19 trigger expression of pathogenic APOL1 via JAK/STAT signaling, resulting in podocyte loss and COVAN phenotype. Here, based on 9 biopsy-proven COVAN cases, we demonstrated for the first time, to the best of our knowledge, that APOL1 protein was abundantly expressed in podocytes and glomerular endothelial cells (GECs) of COVAN kidneys but not in controls. Moreover, a majority of patients with COVAN carried 2 APOL1 risk alleles. We show that recombinant cytokines induced by SARS-CoV-2 acted synergistically to drive APOL1 expression through the JAK/STAT pathway in primary human podocytes, GECs, and kidney micro-organoids derived from a carrier of 2 APOL1 risk alleles, but expression was blocked by a JAK1/2 inhibitor, baricitinib. We demonstrate that cytokine-induced JAK/STAT/APOL1 signaling reduced the viability of kidney organoid podocytes but was rescued by baricitinib. Together, our results support the conclusion that COVID-19-induced cytokines are sufficient to drive COVAN-associated podocytopathy via JAK/STAT/APOL1 signaling and that JAK inhibitors could block this pathogenic process. These findings suggest JAK inhibitors may have therapeutic benefits for managing cytokine-induced, APOL1-mediated podocytopathy.


Subject(s)
COVID-19 , Cytokines , Janus Kinase Inhibitors , Kidney Diseases , Apolipoprotein L1/genetics , Azetidines/pharmacology , COVID-19/drug therapy , COVID-19/metabolism , Cytokines/metabolism , Endothelial Cells/metabolism , Humans , Janus Kinase Inhibitors/pharmacology , Janus Kinases/metabolism , Kidney Diseases/drug therapy , Kidney Diseases/metabolism , Kidney Diseases/virology , Organoids/metabolism , Purines/pharmacology , Pyrazoles/pharmacology , SARS-CoV-2/isolation & purification , STAT Transcription Factors/metabolism , Signal Transduction/drug effects , Sulfonamides/pharmacology
18.
Oxid Med Cell Longev ; 2022: 4525778, 2022.
Article in English | MEDLINE | ID: covidwho-1807689

ABSTRACT

Migrasomes are migration-dependent membrane-bound vesicular structures that contain cellular contents and small vesicles. Migrasomes grow on the tips or intersections of the retraction fibers after cells migrate away. The process of releasing migrasomes into the extracellular space is named as "migracytosis". After releasing, they can be taken up by the surrounding cells, or rupture and further release their contents into the extracellular environment. Physiologically, migrasomes provide regional cues for organ morphogenesis during zebrafish gastrulation and discard the damaged mitochondria in response to mild mitochondrial stresses. Pathologically, migrasomes are released from podocyte during early podocyte stress and/or damage, from platelets after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), from microglia/macrophages of the ischemic brain, and from tumor necrosis factor α (TNFα)-activated endothelial cells (ECs); thus, this newly discovered extracellular vesicle is involved in all these pathological processes. Moreover, migrasomes can modulate the proliferation of cancer cell via lateral transferring mRNA and protein. In this review, we will summarize the biogenesis, release, uptake, and rupture of migrasomes and discuss its biological roles in development, redox signalling, innate immunity and COVID-19, cardio-cerebrovascular diseases, renal diseases, and cancer biology, all of these highlight the importance of migrasomes in modulating body homeostasis and diseases.


Subject(s)
COVID-19 , Zebrafish , Animals , Endothelial Cells , Homeostasis , Humans , SARS-CoV-2
19.
Monoclon Antib Immunodiagn Immunother ; 41(2): 101-109, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1806236

ABSTRACT

Ferrets (Mustela putorius furo) have been used as small animal models to investigate severe acute respiratory syndrome coronaviruses (SARS-CoV and SARS-CoV-2) infections. Pathological analyses of these tissue samples, including those of the lung, are, therefore, essential to understand the pathogenesis of SARS-CoVs and evaluate the action of therapeutic monoclonal antibodies (mAbs) against this disease. However, mAbs that recognize ferret-derived proteins and distinguish between specific cell types, such as lung epithelial cells, are limited. Podoplanin (PDPN) has been identified as an essential marker in lung type I alveolar epithelial cells, kidney podocytes, and lymphatic endothelial cells. In this study, an anti-ferret PDPN (ferPDPN) mAb PMab-292 (mouse IgG1, kappa) was established using the Cell-Based Immunization and Screening (CBIS) method. PMab-292 recognized ferPDPN-overexpressed Chinese hamster ovary-K1 (CHO/ferPDPN) cells by flow cytometry and Western blotting. The kinetic analysis using flow cytometry showed that the KD of PMab-292 for CHO/ferPDPN was 3.4 × 10-8 M. Furthermore, PMab-292 detected lung type I alveolar epithelial cells, lymphatic endothelial cells, and glomerular/Bowman's capsule in the kidney using immunohistochemistry. Hence, these results propose the usefulness of PMab-292 in analyzing ferret-derived tissues for SARS-CoV-2 research.


Subject(s)
Antineoplastic Agents, Immunological , COVID-19 , SARS Virus , Animals , Antibodies, Monoclonal , Antibody Specificity , CHO Cells , Cricetinae , Cricetulus , Endothelial Cells , Epitope Mapping/methods , Ferrets , Kinetics , Membrane Glycoproteins/genetics , Mice , SARS-CoV-2 , Transcription Factors
20.
Stem Cell Reports ; 17(5): 1089-1104, 2022 May 10.
Article in English | MEDLINE | ID: covidwho-1799706

ABSTRACT

Humanized mouse models and mouse-adapted SARS-CoV-2 virus are increasingly used to study COVID-19 pathogenesis, so it is important to learn where the SARS-CoV-2 receptor ACE2 is expressed. Here we mapped ACE2 expression during mouse postnatal development and in adulthood. Pericytes in the CNS, heart, and pancreas express ACE2 strongly, as do perineurial and adrenal fibroblasts, whereas endothelial cells do not at any location analyzed. In a number of other organs, pericytes do not express ACE2, including in the lung where ACE2 instead is expressed in bronchial epithelium and alveolar type II cells. The onset of ACE2 expression is organ specific: in bronchial epithelium already at birth, in brain pericytes before, and in heart pericytes after postnatal day 10.5. Establishing the vascular localization of ACE2 expression is central to correctly interpret data from modeling COVID-19 in the mouse and may shed light on the cause of vascular COVID-19 complications.


Subject(s)
Angiotensin-Converting Enzyme 2 , COVID-19 , Pericytes , Angiotensin-Converting Enzyme 2/metabolism , Animals , COVID-19/complications , Cardiovascular Diseases/virology , Endothelial Cells , Mice , Pericytes/metabolism , SARS-CoV-2
SELECTION OF CITATIONS
SEARCH DETAIL