scholarly journals Severe Acute Respiratory Syndrome Coronavirus Infection Causes Neuronal Death in the Absence of Encephalitis in Mice Transgenic for Human ACE2

2008 ◽  
Vol 82 (15) ◽  
pp. 7264-7275 ◽  
Author(s):  
Jason Netland ◽  
David K. Meyerholz ◽  
Steven Moore ◽  
Martin Cassell ◽  
Stanley Perlman
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Cell Receptor ◽  
Neurological Sequelae ◽  
Angiotensin Converting Enzyme 2 ◽  
Brain Infection ◽  
Host Cell Receptor ◽  
Coronavirus Infection ◽  
The Brain ◽  
Major Target

ABSTRACT Infection of humans with the severe acute respiratory syndrome coronavirus (SARS-CoV) results in substantial morbidity and mortality, with death resulting primarily from respiratory failure. While the lungs are the major site of infection, the brain is also infected in some patients. Brain infection may result in long-term neurological sequelae, but little is known about the pathogenesis of SARS-CoV in this organ. We previously showed that the brain was a major target organ for infection in mice that are transgenic for the SARS-CoV receptor (human angiotensin-converting enzyme 2). Herein, we use these mice to show that virus enters the brain primarily via the olfactory bulb, and infection results in rapid, transneuronal spread to connected areas of the brain. This extensive neuronal infection is the main cause of death because intracranial inoculation with low doses of virus results in a uniformly lethal disease even though little infection is detected in the lungs. Death of the animal likely results from dysfunction and/or death of infected neurons, especially those located in cardiorespiratory centers in the medulla. Remarkably, the virus induces minimal cellular infiltration in the brain. Our results show that neurons are a highly susceptible target for SARS-CoV and that only the absence of the host cell receptor prevents severe murine brain disease.

scholarly journals Endothelial Dysfunction in the Brain

Stroke ◽  
2021 ◽  
Author(s):  
Maithili Sashindranath ◽  
Harshal H. Nandurkar
Keyword(s):  
Endothelial Cells ◽  
Severe Acute Respiratory Syndrome ◽  
Neurological Sequelae ◽  
Angiotensin Converting Enzyme 2 ◽  
Cerebrovascular Complications ◽  
Hemostatic Markers ◽  
Tract Infections ◽  
And Function ◽  
The Brain ◽  
Major Target

The Coronavirus disease 2019 (COVID)-19 pandemic has already affected millions worldwide, with a current mortality rate of 2.2%. While it is well-established that severe acute respiratory syndrome-coronavirus-2 causes upper and lower respiratory tract infections, a number of neurological sequelae have now been reported in a large proportion of cases. Additionally, the disease causes arterial and venous thromboses including pulmonary embolism, myocardial infarction, and a significant number of cerebrovascular complications. The increasing incidence of large vessel ischemic strokes as well as intracranial hemorrhages, frequently in younger individuals, and associated with increased morbidity and mortality, has raised questions as to why the brain is a major target of the disease. COVID-19 is characterized by hypercoagulability with alterations in hemostatic markers including high D-dimer levels, which are a prognosticator of poor outcome. Together with findings of fibrin-rich microthrombi, widespread extracellular fibrin deposition in affected various organs and hypercytokinemia, this suggests that COVID-19 is more than a pulmonary viral infection. Evidently, COVID-19 is a thrombo-inflammatory disease. Endothelial cells that constitute the lining of blood vessels are the primary targets of a thrombo-inflammatory response, and severe acute respiratory syndrome coronavirus 2 also directly infects endothelial cells through the ACE2 (angiotensin-converting enzyme 2) receptor. Being highly heterogeneous in their structure and function, differences in the endothelial cells may govern the susceptibility of organs to COVID-19. Here, we have explored how the unique characteristics of the cerebral endothelium may be the underlying reason for the increased rates of cerebrovascular pathology associated with COVID-19.

scholarly journals Increasing Host Cellular Receptor—Angiotensin-Converting Enzyme 2 (ACE2) Expression by Coronavirus may Facilitate 2019-nCoV Infection

2020 ◽  
Author(s):  
Pei-Hui Wang ◽  
Yun Cheng
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Emerging Infectious Diseases ◽  
Cell Receptor ◽  
Host Cells ◽  
Cellular Receptor ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Host Cell Receptor ◽  
Coronavirus Infection ◽  
Entry Receptor

AbstractThe ongoing outbreak of a new coronavirus (2019-nCoV) causes an epidemic of acute respiratory syndrome in humans. 2019-nCoV rapidly spread to national regions and multiple other countries, thus, pose a serious threat to public health. Recent studies show that spike (S) proteins of 2019-nCoV and SARS-CoV may use the same host cell receptor called angiotensin-converting enzyme 2 (ACE2) for entering into host cells. The affinity between ACE2 and 2019-nCoV S is much higher than ACE2 binding to SARS-CoV S protein, explaining that why 2019-nCoV seems to be more readily transmitted from the human to human. Here, we reported that ACE2 can be significantly upregulated after infection of various viruses including SARS-CoV and MERS-CoV. Basing on findings here, we propose that coronavirus infection can positively induce its cellular entry receptor to accelerate their replication and spread, thus drugs targeting ACE2 expression may be prepared for the future emerging infectious diseases caused by this cluster of viruses.

scholarly journals Lethal Infection of K18-hACE2 Mice Infected with Severe Acute Respiratory Syndrome Coronavirus

2006 ◽  
Vol 81 (2) ◽  
pp. 813-821 ◽  
Author(s):  
Paul B. McCray ◽  
Lecia Pewe ◽  
Christine Wohlford-Lenane ◽  
Melissa Hickey ◽  
Lori Manzel ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Economic Losses ◽  
Potential Threat ◽  
Angiotensin Converting Enzyme 2 ◽  
Antiviral Therapies ◽  
Brain Infection ◽  
Cytokines And Chemokines ◽  
Lethal Infection ◽  
Novel Coronavirus ◽  
The Brain

ABSTRACT The severe acute respiratory syndrome (SARS), caused by a novel coronavirus (SARS-CoV), resulted in substantial morbidity, mortality, and economic losses during the 2003 epidemic. While SARS-CoV infection has not recurred to a significant extent since 2003, it still remains a potential threat. Understanding of SARS and development of therapeutic approaches have been hampered by the absence of an animal model that mimics the human disease and is reproducible. Here we show that transgenic mice that express the SARS-CoV receptor (human angiotensin-converting enzyme 2 [hACE2]) in airway and other epithelia develop a rapidly lethal infection after intranasal inoculation with a human strain of the virus. Infection begins in airway epithelia, with subsequent alveolar involvement and extrapulmonary virus spread to the brain. Infection results in macrophage and lymphocyte infiltration in the lungs and upregulation of proinflammatory cytokines and chemokines in both the lung and the brain. This model of lethal infection with SARS-CoV should be useful for studies of pathogenesis and for the development of antiviral therapies.

scholarly journals Melatonin drugs inhibit SARS-CoV-2 entry into the brain and virus-induced damage of cerebral small vessels

2022 ◽  
Author(s):  
Erika Cecon ◽  
Daniela Fernandois ◽  
Nicolas Renault ◽  
Caio Fernando Ferreira Coelho ◽  
Jan Wenzel ◽  
...  
Keyword(s):  
Complex Disease ◽  
Immune Cell ◽  
Neurological Symptoms ◽  
Brain Inflammation ◽  
Angiotensin Converting Enzyme 2 ◽  
Small Vessels ◽  
Brain Infection ◽  
Short And Long Term ◽  
The Brain

COVID-19 is a complex disease with short- and long-term respiratory, inflammatory and neurological symptoms that are triggered by the infection with SARS-CoV-2. Invasion of the brain by SARS-CoV-2 has been observed in humans and is postulated to be involved in post COVID condition. Brain infection is particularly pronounced in the K18-hACE2 mouse model of COVID-19. Here, we show that treatment of K18-hACE2 mice with melatonin and two melatonin-derived marketed drugs, agomelatine and ramelteon, prevent SARS-CoV-2 entry in the brain thereby reducing virus-induced damage of small cerebral vessels, immune cell infiltration and brain inflammation. Brain entry of SARS-CoV-2 through endothelial cells is prevented by melatonin through allosteric binding to human angiotensin-converting enzyme 2 (ACE2), which interferes with the cell entry receptor function of ACE2 for SARS-CoV-2. Our findings open new perspectives for the repurposing of melatonergic drugs in the prevention of brain infection by SARS-CoV-2 and COVID-19-related long-term neurological symptoms.

scholarly journals A case of severe acute respiratory syndrome coronavirus 2 with acute thrombotic cerebral infarction and generalized thrombosis

2021 ◽  
pp. 405-408
Author(s):  
Sylvia Nikolaeva Genova ◽  
Nikolaeva Genova ◽  
Mina Miroslavova Pencheva ◽  
Alexander Georgiev Ivanov
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Cerebral Infarction ◽  
Viral Pneumonia ◽  
Autopsy Case ◽  
Full Spectrum ◽  
Histological Changes ◽  
Large Size ◽  
Thrombotic Complications ◽  
Coronavirus Infection ◽  
The Brain

The full spectrum of coronavirus disease 2019 (COVID-19) has not been fully described yet. COVID-19 is associated with a high risk of thrombotic complications such as venous thromboembolism and cerebrovascular disease. Here, we report an autopsy case of a 55-year-old woman diagnosed with severe viral pneumonia complicated by acute cerebral infarction and venous and arterial thrombosis in different organs. The patient died due to severe acute respiratory syndrome coronavirus 2. Macroscopically and histologically, in addition to viral pneumonia and diffuse hemorrhages, fibrin clots were found in arteries and venous vessels of medium and large size in the brain, lungs, and pancreas. Propagation of cerebrovascular thrombosis has led to extensive cerebral infarction. The dating of this infarction, according to the macroscopical findings and the histological changes, was between 24 and 48 h before death. This case confirms the hypothesis on the risk of generalized arterial and venous thromboses in coronavirus infection.

scholarly journals An ultrapotent synthetic nanobody neutralizes SARS-CoV-2 by stabilizing inactive Spike

Science ◽  
2020 ◽  
pp. eabe3255 ◽  
Author(s):  
Michael Schoof ◽  
Bryan Faust ◽  
Reuben A. Saunders ◽  
Smriti Sangwan ◽  
Veronica Rezelj ◽  
...  
Keyword(s):  
Cell Receptor ◽  
Affinity Maturation ◽  
Host Cells ◽  
Spike Protein ◽  
Airway Epithelia ◽  
Angiotensin Converting Enzyme 2 ◽  
Inactive Conformation ◽  
Binding Domains ◽  
Host Cell Receptor ◽  
Yeast Surface

The SARS-CoV-2 virus enters host cells via an interaction between its Spike protein and the host cell receptor angiotensin converting enzyme 2 (ACE2). By screening a yeast surface-displayed library of synthetic nanobody sequences, we developed nanobodies that disrupt the interaction between Spike and ACE2. Cryogenic electron microscopy (cryo-EM) revealed that one nanobody, Nb6, binds Spike in a fully inactive conformation with its receptor binding domains (RBDs) locked into their inaccessible down-state, incapable of binding ACE2. Affinity maturation and structure-guided design of multivalency yielded a trivalent nanobody, mNb6-tri, with femtomolar affinity for Spike and picomolar neutralization of SARS-CoV-2 infection. mNb6-tri retains function after aerosolization, lyophilization, and heat treatment, which enables aerosol-mediated delivery of this potent neutralizer directly to the airway epithelia.

scholarly journals Differential Virological and Immunological Outcome of Severe Acute Respiratory Syndrome Coronavirus Infection in Susceptible and Resistant Transgenic Mice Expressing Human Angiotensin-Converting Enzyme 2

2009 ◽  
Vol 83 (11) ◽  
pp. 5451-5465 ◽  
Author(s):  
Naoko Yoshikawa ◽  
Tomoki Yoshikawa ◽  
Terence Hill ◽  
Cheng Huang ◽  
Douglas M. Watts ◽  
...  
Keyword(s):  
T Cells ◽  
Severe Acute Respiratory Syndrome ◽  
Angiotensin Converting Enzyme ◽  
Viral Infection ◽  
Inflammatory Responses ◽  
Fatal Outcome ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Inflammatory Infiltrates ◽  
The Brain

ABSTRACT We previously reported that transgenic (Tg) mice expressing human angiotensin-converting enzyme 2 (hACE2), the receptor for severe acute respiratory syndrome coronavirus (SARS-CoV), were highly susceptible to SARS-CoV infection, which resulted in the development of disease of various severity and even death in some lineages. In this study, we further characterized and compared the pathogeneses of SARS-CoV infection in two of the most stable Tg lineages, AC70 and AC22, representing those susceptible and resistant to the lethal SARS-CoV infection, respectively. The kinetics of virus replication and the inflammatory responses within the lungs and brains, as well as the clinical and pathological outcomes, were assessed in each lineage. In addition, we generated information on lymphocyte subsets and mitogen-mediated proliferation of splenocytes. We found that while both lineages were permissive to SARS-CoV infection, causing elevated secretion of many inflammatory mediators within the lungs and brains, viral infection appeared to be more intense in AC70 than in AC22 mice, especially in the brain. Moreover, such infection was accompanied by a more profound immune suppression in the former, as evidenced by the extensive loss of T cells, compromised responses to concanavalin A stimulation, and absence of inflammatory infiltrates within the brain. We also found that CD8+ T cells were partially effective in attenuating the pathogenesis of SARS-CoV infection in lethality-resistant AC22 mice. Collectively, our data revealed a more intense viral infection and immunosuppression in AC70 mice than in AC22 mice, thereby providing us with an immunopathogenic basis for the fatal outcome of SARS-CoV infection in the AC70 mice.

scholarly journals Geranium and Lemon Essential Oils and Their Active Compounds Downregulate Angiotensin-Converting Enzyme 2 (ACE2), a SARS-CoV-2 Spike Receptor-Binding Domain, in Epithelial Cells

Plants ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 770 ◽  
Author(s):  
K. J. Senthil Kumar ◽  
M. Gokila Vani ◽  
Chung-Shuan Wang ◽  
Chia-Chi Chen ◽  
Yu-Chien Chen ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Angiotensin Converting Enzyme ◽  
Essential Oils ◽  
Cell Receptor ◽  
Gas Chromatography Mass Spectrometry ◽  
Converting Enzyme ◽  
Inhibitory Effects ◽  
Angiotensin Converting Enzyme 2 ◽  
Host Cell Receptor ◽  
Lemon Oil

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also known as coronavirus disease-2019 (COVID-19), is a pandemic disease that has been declared as modern history’s gravest health emergency worldwide. Until now, no precise treatment modality has been developed. The angiotensin-converting enzyme 2 (ACE2) receptor, a host cell receptor, has been found to play a crucial role in virus cell entry; therefore, ACE2 blockers can be a potential target for anti-viral intervention. In this study, we evaluated the ACE2 inhibitory effects of 10 essential oils. Among them, geranium and lemon oils displayed significant ACE2 inhibitory effects in epithelial cells. In addition, immunoblotting and qPCR analysis also confirmed that geranium and lemon oils possess potent ACE2 inhibitory effects. Furthermore, the gas chromatography-mass spectrometry (GC–MS) analysis displayed 22 compounds in geranium oil and 9 compounds in lemon oil. Citronellol, geraniol, and neryl acetate were the major compounds of geranium oil and limonene that represented major compound of lemon oil. Next, we found that treatment with citronellol and limonene significantly downregulated ACE2 expression in epithelial cells. The results suggest that geranium and lemon essential oils and their derivative compounds are valuable natural anti-viral agents that may contribute to the prevention of the invasion of SARS-CoV-2/COVID-19 into the human body.

Development and Implementation of a Brain Rest Protocol in Nonintellectually Challenged Youth With Head-Banging Behaviors

2020 ◽  
Vol 26 (3) ◽  
pp. 282-287
Author(s):  
Lori Keough ◽  
Susan Gardner ◽  
Alyssa Kirby
Keyword(s):  
Traumatic Brain Injury ◽  
Athletic Injury ◽  
Nursing Assessment ◽  
Neurological Sequelae ◽  
Self Injury ◽  
Intervention Protocol ◽  
Strength Based ◽  
The Brain

INTRODUCTION: Concussions as a result of mild traumatic brain injury (MTBI) in youth are often associated with athletic injury; however, they can also occur as a result of intentional self-injury by head banging. Despite the known neurological sequelae secondary to MTBI, assessment, interventions, and consequences of head banging in the nonintellectually disabled populations have not been well studied. AIMS: The intent of this nurse-led intervention was to develop a brain rest protocol at a residential treatment program serving youth who were between 12 and 19 years old in order to improve the quality of care and moderate negative sequelae resulting from MTBI. METHODS: A nursing assessment guided by an adaptation of the acute concussion evaluation and a strength-based intervention protocol was developed and applied to youth who engage in head banging. RESULTS: The result was a protocol that defined the process by which a youth would be assessed and treated after head banging. There are no outcome measures that would assist to measure the effectiveness of this intervention in the short or long term. CONCLUSION: This intervention filled a need for improved assessment and appropriate interventions in youth with head-banging behavior. It is feasible that the assessment and implementation of the brain rest protocol is the first step in understanding how to best evaluate and manage the sequelae of intentional head banging resulting from MTBI.

scholarly journals Characterisation of a novel ACE2-based therapeutic with enhanced rather than reduced activity against SARS-CoV-2 variants.

2021 ◽  
Author(s):  
Mathieu Ferrari ◽  
Leila Mekkaoui ◽  
F. Tudor Ilca ◽  
Zulaikha Akbar ◽  
Reyisa Bughda ◽  
...  
Keyword(s):  
Viral Infections ◽  
Scale Up ◽  
Renin Angiotensin System ◽  
Cell Receptor ◽  
Biophysical Properties ◽  
Angiotensin Converting Enzyme 2 ◽  
Host Cell Receptor ◽  
System 2 ◽  
Reduced Activity ◽  
Reduced Risk

The human angiotensin-converting enzyme 2 acts as the host cell receptor for SARS-CoV-2 and the other members of the Coronaviridae family SARS-CoV-1 and HCoV-NL63. Here we report the biophysical properties of the SARS-CoV-2 spike variants D614G, B.1.1.7, B.1.351 and P.1 with affinities to the ACE2 receptor and infectivity capacity, revealing weaknesses in the developed neutralising antibody approaches. Furthermore, we report a pre-clinical characterisation package for a soluble receptor decoy engineered to be catalytically inactive and immunologically inert, with broad neutralisation capacity, that represents an attractive therapeutic alternative in light of the mutational landscape of COVID-19. This construct efficiently neutralised four SARS-CoV-2 variants of concern. The decoy also displays antibody-like biophysical properties and manufacturability, strengthening its suitability as a first-line treatment option in prophylaxis or therapeutic regimens for COVID-19 and related viral infections. IMPORTANCE Mutational drift of SARS-CoV-2 risks rendering both therapeutics and vaccines less effective. Receptor decoy strategies utilising soluble human ACE2 may overcome the risk of viral mutational escape since mutations disrupting viral interaction with the ACE2 decoy will by necessity decrease virulence thereby preventing meaningful escape. The solution described here of a soluble ACE2 receptor decoy is significant for the following reasons: While previous ACE2-based therapeutics have been described, ours has novel features including (1) mutations within ACE2 to remove catalytical activity and systemic interference with the renin/angiotensin system; (2) abrogated FcγR engagement, reduced risk of antibody-dependent enhancement of infection and reduced risk of hyperinflammation, and (3) streamlined antibody-like purification process and scale-up manufacturability indicating that this receptor decoy could be produced quickly and easily at scale. Finally, we demonstrate that ACE2-based therapeutics confer a broad-spectrum neutralisation potency for ACE2-tropic viruses, including SARS-CoV-2 variants of concern in contrast to therapeutic mAb.

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