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 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 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.

COVID-19, the Brain, and the Future: Is Infection by the Novel Coronavirus a Harbinger of Neurodegeneration?

2021 ◽  
Vol 21 ◽  
Author(s):  
Adejoke Onaolapo ◽  
Olakunle Onaolapo
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Severe Acute Respiratory Syndrome ◽  
Neurodegenerative Diseases ◽  
Central Nervous System Involvement ◽  
The Novel ◽  
Novel Coronavirus ◽  
The Impact ◽  
The Brain

: The possible impact of viral infections on the development or pathogenesis of neurodegenerative disorders remains largely unknown. However, there have been reports associating the influenza virus pandemic and long-term infection with the Japanese encephalitis virus with the development of post-encephalitic Parkinsonism or von Economo encephalitis. In the last one year plus, there has been a worldwide pandemic arising from infection with the novel coronavirus or severe acute respiratory syndrome coronavirus (SARS-CoV)-2 which causes a severe acute respiratory syndrome that has become associated with central nervous system symptoms or complications. Its possible central nervous system involvement is in line with emerging scientific evidence which shows that the human respiratory coronaviruses can enter the brain, infect neural cells, persist in the brain, and cause activation of myelin-reactive T cells. Currently, there is a dearth of scientific information on the acute or possible long-term impact of infection with SARS-CoV-2 on the development of dementias and/or neurodegenerative diseases. This is not unrelated to the fact that the virus is ‘new’, and its effects on humans are still being studied. This narrative review examines extant literature for the impact of corona virus infections on the brain; as it considers the possibility that coronavirus disease 2019 (COVID-19) could increase the risk for the development of neurodegenerative diseases or hasten their progression.

scholarly journals Variation in predicted COVID-19 risk among lemurs and lorises

2021 ◽  
Author(s):  
Amanda D. Melin ◽  
Joseph D. Orkin ◽  
Mareike C. Janiak ◽  
Alejandro Valenzuela ◽  
Lukas Kuderna ◽  
...  
Keyword(s):  
Sampling Effort ◽  
The Novel ◽  
Infection Rates ◽  
Potential Threat ◽  
Angiotensin Converting Enzyme 2 ◽  
Rare And Endangered ◽  
Novel Coronavirus ◽  
Taxonomic Groups ◽  
Viral Target ◽  
Amino Acid Conservation

AbstractThe novel coronavirus SARS-CoV-2, which in humans leads to the disease COVID-19, has caused global disruption and more than 1.5 million fatalities since it first emerged in late 2019. As we write, infection rates are currently at their highest point globally and are rising extremely rapidly in some areas due to more infectious variants. The primary viral target is the cellular receptor angiotensin-converting enzyme-2 (ACE2). Recent sequence analyses of the ACE2 gene predicts that many nonhuman primates are also likely to be highly susceptible to infection. However, the anticipated risk is not equal across the Order. Furthermore, some taxonomic groups show high ACE2 amino acid conservation, while others exhibit high variability at this locus. As an example of the latter, analyses of strepsirrhine primate ACE2 sequences to date indicate large variation among lemurs and lorises compared to other primate clades despite low sampling effort. Here, we report ACE2 gene and protein sequences for 71 individual strepsirrhines, spanning 51 species and 19 genera. Our study reinforces previous results and finds additional variability in other strepsirrhine species, and suggests several clades of lemurs have high potential susceptibility to SARS-CoV-2 infection. Troublingly, some species, including the rare and Endangered aye-aye (Daubentonia madagascariensis), as well as those in the genera Avahi and Propithecus, may be at high risk. Given that lemurs are endemic to Madagascar and among the primates at highest risk of extinction globally, further understanding of the potential threat of COVID-19 to their health should be a conservation priority. All feasible actions should be taken to limit their exposure to SARS-CoV-2.

scholarly journals Expression of the ACE2 Virus Entry Protein in the Nervus Terminalis Reveals the Potential for an Alternative Route to Brain Infection in COVID-19

2021 ◽  
Vol 15 ◽  
Author(s):  
Katarzyna Bilinska ◽  
Christopher S. von Bartheld ◽  
Rafal Butowt
Keyword(s):  
Virus Entry ◽  
Olfactory Nerve ◽  
Alternative Route ◽  
Angiotensin Converting Enzyme 2 ◽  
Nervus Terminalis ◽  
Brain Infection ◽  
Potential Alternative ◽  
Receptor Neurons ◽  
The Brain ◽  
Entry Receptor

Previous studies suggested that the SARS-CoV-2 virus may gain access to the brain by using a route along the olfactory nerve. However, there is a general consensus that the obligatory virus entry receptor, angiotensin converting enzyme 2 (ACE2), is not expressed in olfactory receptor neurons, and the timing of arrival of the virus in brain targets is inconsistent with a neuronal transfer along olfactory projections. We determined whether nervus terminalis neurons and their peripheral and central projections should be considered as a potential alternative route from the nose to the brain. Nervus terminalis neurons in postnatal mice were double-labeled with antibodies against ACE2 and two nervus terminalis markers, gonadotropin-releasing hormone (GnRH) and choline acetyltransferase (CHAT). We show that a small fraction of CHAT-labeled nervus terminalis neurons, and the large majority of GnRH-labeled nervus terminalis neurons with cell bodies in the region between the olfactory epithelium and the olfactory bulb express ACE2 and cathepsins B and L. Nervus terminalis neurons therefore may provide a direct route for the virus from the nasal epithelium, possibly via innervation of Bowman’s glands, to brain targets, including the telencephalon and diencephalon. This possibility needs to be examined in suitable animal models and in human tissues.

scholarly journals Expression of the ACE2 virus entry protein in the nervus terminalis suggests an alternative route for brain infection in COVID-19

2021 ◽  
Author(s):  
Katarzyna Bilinska ◽  
Christopher S. von Bartheld ◽  
Rafal Butowt
Keyword(s):  
Virus Entry ◽  
Olfactory Nerve ◽  
Alternative Route ◽  
Angiotensin Converting Enzyme 2 ◽  
Nervus Terminalis ◽  
Brain Infection ◽  
Receptor Neurons ◽  
The Brain ◽  
Entry Receptor ◽  
Gain Access

AbstractPrevious studies suggested that the SARS-CoV-2 virus may gain access to the brain by using a route along the olfactory nerve. However, there is a general consensus that the obligatory virus entry receptor, angiotensin converting enzyme 2 (ACE2), is not expressed in olfactory receptor neurons, and the timing of arrival of the virus in brain targets is inconsistent with a neuronal transfer along olfactory projections. We determined whether nervus terminalis neurons and their peripheral and central projections may provide an alternative route from the nose to the brain. Nervus terminalis neurons were double-labeled with antibodies against ACE2 and nervus terminalis markers in postnatal mice. We show that most nervus terminalis neurons with cell bodies in the region between the olfactory epithelium and the olfactory bulb express ACE2, and therefore may provide a direct route for the virus from the nasal epithelium and Bowman’s glands to brain targets, including the telencephalon and diencephalon.

scholarly journals Novel coronavirus (severe acute respiratory syndrome coronavirus 2) as threat to general and reproductive health: Challenges and research needs

2021 ◽  
Vol 2 ◽  
pp. 19-25
Author(s):  
Pradeep Kumar ◽  
Rajeev Singh
Keyword(s):  
Reproductive Health ◽  
Severe Acute Respiratory Syndrome ◽  
Male Fertility ◽  
Research Needs ◽  
Global Public Health ◽  
Future Prospects ◽  
Angiotensin Converting Enzyme 2 ◽  
Major Threat ◽  
Novel Coronavirus ◽  
Major Factors

Coronavirus disease (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 and emerged as a major threat to global public health. Along with the respiratory system, COVID-19 may also affect male fertility, family planning, and pregnancy. Expression of angiotensin-converting enzyme-2 in testis on the entry of viral particle and fever is two major factors responsible for reduced fertility. Children, pregnant women, and older people are more susceptible to infection. Males are more susceptible to infection and morbidity caused due to COVID-19. In this review, the current global scenario, clinical infestations, possible effect on reproductive health, and future prospects of COVID-19 are elaborated.

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 Structural Analysis of Major Species Barriers between Humans and Palm Civets for Severe Acute Respiratory Syndrome Coronavirus Infections

2008 ◽  
Vol 82 (14) ◽  
pp. 6984-6991 ◽  
Author(s):  
Fang Li
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Human Cells ◽  
Structural Basis ◽  
Specific Interactions ◽  
Receptor Binding Domain ◽  
Salt Bridges ◽  
Angiotensin Converting Enzyme 2 ◽  
Major Species ◽  
Novel Coronavirus ◽  
Receptor Interface

ABSTRACT It is believed that a novel coronavirus, severe acute respiratory syndrome coronavirus (SARS-CoV), was passed from palm civets to humans and caused the epidemic of SARS in 2002 to 2003. The major species barriers between humans and civets for SARS-CoV infections are the specific interactions between a defined receptor-binding domain (RBD) on a viral spike protein and its host receptor, angiotensin-converting enzyme 2 (ACE2). In this study a chimeric ACE2 bearing the critical N-terminal helix from civet and the remaining peptidase domain from human was constructed, and it was shown that this construct has the same receptor activity as civet ACE2. In addition, crystal structures of the chimeric ACE2 complexed with RBDs from various human and civet SARS-CoV strains were determined. These structures, combined with a previously determined structure of human ACE2 complexed with the RBD from a human SARS-CoV strain, have revealed a structural basis for understanding the major species barriers between humans and civets for SARS-CoV infections. They show that the major species barriers are determined by interactions between four ACE2 residues (residues 31, 35, 38, and 353) and two RBD residues (residues 479 and 487), that early civet SARS-CoV isolates were prevented from infecting human cells due to imbalanced salt bridges at the hydrophobic virus/receptor interface, and that SARS-CoV has evolved to gain sustained infectivity for human cells by eliminating unfavorable free charges at the interface through stepwise mutations at positions 479 and 487. These results enhance our understanding of host adaptations and cross-species infections of SARS-CoV and other emerging animal viruses.

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