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 The olfactory nerve is not a likely route to brain infection in COVID-19: a critical review of data from humans and animal models

2021 ◽  
Author(s):  
Rafal Butowt ◽  
Nicolas Meunier ◽  
Bertrand Bryche ◽  
Christopher S. von Bartheld
Keyword(s):  
Animal Models ◽  
Virus Entry ◽  
Olfactory Nerve ◽  
Olfactory Receptor Neurons ◽  
Current Evidence ◽  
Olfactory Neurons ◽  
Brain Infection ◽  
Receptor Neurons ◽  
Alternative Routes ◽  
The Brain

AbstractOne of the most frequent symptoms of COVID-19 is the loss of smell and taste. Based on the lack of expression of the virus entry proteins in olfactory receptor neurons, it was originally assumed that the new coronavirus (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2) does not infect olfactory neurons. Recent studies have reported otherwise, opening the possibility that the virus can directly infect the brain by traveling along the olfactory nerve. Multiple animal models have been employed to assess mechanisms and routes of brain infection of SARS-CoV-2, often with conflicting results. We here review the current evidence for an olfactory route to brain infection and conclude that the case for infection of olfactory neurons is weak, based on animal and human studies. Consistent brain infection after SARS-CoV-2 inoculation in mouse models is only seen when the virus entry proteins are expressed abnormally, and the timeline and progression of rare neuro-invasion in these and in other animal models points to alternative routes to the brain, other than along the olfactory projections. COVID-19 patients can be assured that loss of smell does not necessarily mean that the SARS-CoV-2 virus has gained access to and has infected their brains.

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 Characterization of spike glycoprotein of 2019-nCoV on virus entry and its immune cross-reactivity with spike glycoprotein of SARS-CoV  

2020 ◽  
Author(s):  
Xiuyuan Ou ◽  
Yan Liu ◽  
Xiaobo Lei ◽  
Pei Li ◽  
Dan Mi ◽  
...  
Keyword(s):  
Virus Entry ◽  
Cathepsin L ◽  
Cross Reactivity ◽  
Spike Glycoprotein ◽  
S Protein ◽  
Angiotensin Converting Enzyme 2 ◽  
Dependent Cell ◽  
Cross Neutralization ◽  
Entry Receptor

Abstract Since beginning of this century, there have already been three zoonotic outbreaks caused by beta coronaviruses (CoV), SARS-CoV in 2002-2003, MERS-CoV in 2012, and the newly identified 2019-nCoV in late 2019, Wuhan, China. As to Feb 10th, 2020, there are over 40,000 confirmed cases and over 900 deaths. However, little is known about the biology of this newly emerged virus. Here we developed a lentiviral based pseudovirus system for S protein of 2019-nCoV to study virus entry in BSL2 settings. First, we confirmed that human angiotensin converting enzyme 2 (hACE2) is the main entry receptor for 2019-nCoV. Second, we found that 2019-nCoV S protein mediated entry on 293/hACE2 cells was mainly through endocytosis, and PIKfyve, TPC2, and cathepsin L are critical for virus entry. Third, 2019-nCoV S protein is less stable than SARS-CoV, and it could trigger protease-independent and receptor dependent cell-cell fusion, which might help virus rapidly spread from cell to cell. Finally and more importantly, polyclonal anti-SARS S1 antibodies T62 effectively inhibited entry of SARS-CoV S pseudovirions, but almost had no effect on entry of 2019-nCoV S pseudovirions. Further studies using sera from one recovered SARS-CoV patient and five 2019-nCoV patients showed that there was only limited cross-neutralization activities between SARS-CoV and 2019-nCoV sera, suggesting that recovery from one infection might not protect against the other. Our results present potential targets for development of drugs and vaccines for 2019-nCoV.

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 The Rhinolophus affinis bat ACE2 and multiple animal orthologs are functional receptors for bat coronavirus RaTG13 and SARS-CoV-2

2020 ◽  
Author(s):  
Pei Li ◽  
Ruixuan Guo ◽  
Yan Liu ◽  
Yintgtao Zhang ◽  
Jiaxin Hu ◽  
...  
Keyword(s):  
Animal Species ◽  
Virus Entry ◽  
Receptor Binding Domain ◽  
Converting Enzyme ◽  
S Protein ◽  
Angiotensin Converting Enzyme 2 ◽  
Sequence Identity ◽  
Rhinolophus Affinis ◽  
Entry Receptor ◽  
Bat Coronavirus

AbstractBat coronavirus (CoV) RaTG13 shares the highest genome sequence identity with SARS-CoV-2 among all known coronaviruses, and also uses human angiotensin converting enzyme 2 (hACE2) for virus entry. Thus, SARS-CoV-2 is thought to have originated from bat. However, whether SARS-CoV-2 emerged from bats directly or through an intermediate host remains elusive. Here, we found that Rhinolophus affinis bat ACE2 (RaACE2) is an entry receptor for both SARS-CoV-2 and RaTG13, although RaACE2 binding to the receptor binding domain (RBD) of SARS-CoV-2 is markedly weaker than that of hACE2. We further evaluated the receptor activities of ACE2s from additional 16 diverse animal species for RaTG13, SARS-CoV, and SARS-CoV-2 in terms of S protein binding, membrane fusion, and pseudovirus entry. We found that the RaTG13 spike (S) protein is significantly less fusogenic than SARS-CoV and SARS-CoV-2, and seven out of sixteen different ACE2s function as entry receptors for all three viruses, indicating that all three viruses might have broad host rages. Of note, RaTG13 S pseudovirions can use mouse, but not pangolin ACE2, for virus entry, whereas SARS-CoV-2 S pseudovirions can use pangolin, but limited for mouse, ACE2s enter cells. Mutagenesis analysis revealed that residues 484 and 498 in RaTG13 and SARS-CoV-2 S proteins play critical roles in recognition of mouse and human ACE2. Finally, two polymorphous Rhinolophous sinicus bat ACE2s showed different susceptibilities to virus entry by RaTG13 and SARS-CoV-2 S pseudovirions, suggesting possible coevolution. Our results offer better understanding of the mechanism of coronavirus entry, host range, and virus-host coevolution.

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.

Angiotensin Converting Enzyme 2 (ACE2) Expression in the Visual System

2021 ◽  
Author(s):  
James M. Hill ◽  
Christian Clement ◽  
L. Arceneaux ◽  
Walter Lukiw
Keyword(s):  
Signal Processing ◽  
Angiotensin Converting Enzyme ◽  
Occipital Lobe ◽  
Cell Types ◽  
Receptor Expression ◽  
Host Cells ◽  
Visual Signal ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
The Brain

Abstract Background: Multiple lines of evidence currently indicate that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)gains entry into human host cells via a high-affinity interaction with the angiotensin-converting enzyme 2 (ACE2) transmembrane receptor. Research has further shown the widespread expression of the ACE2 receptor on the surface of many different immune, non-immune and neural host cell types, and that SARS-CoV-2 has there markable capability to attack many different types of human-host cells simultaneously. One principal neuroanatomical region for highACE2 expression patterns occurs in the brainstem, an area of the brain containing regulatory centers for respiration, and this may in part explain the predisposition of many COVID-19 patients to respiratory distress. Early studies also indicated extensive ACE2 expression in the whole eye and the brain’s visual circuitry. In this study we analyzed ACE2 receptor expression at the mRNA and protein level in multiple cell types involved in human vision, including cell types of the external eye and several deep brain regions known to be involved in the processing of visual signals.Methods: ACE2 mRNA and protein analysis; multiple eye and brain cells and tissues; gamma32P-adenosine tri-phosphate ([γ-32P]dATP) radiolabeled probes; Northern analysis; ELISA.Results: The four main findings were: (i)that many different optical and neural cell types of the human visual system provide receptors essential for SARS-CoV-2 invasion; (ii)the remarkable ubiquity of ACE2 presence in cells of the eye and anatomical regions of the brain involved in visual signal processing; (iii)that ACE2 receptor expression in different ocular cell types and visual processing centers of the brain provide multiple compartments for SARS-CoV-2 infiltration; and (iv)a gradient of increasing ACE2 expression from the anterior surface of the eye to the visual signal processing areas of the occipital lobe and the primary visual neocortex.Conclusion: A gradient of ACE2 expression from the eye surface to the occipital lobe provide the SARS-CoV-2 virus a novel pathway from the outer eye into deeper anatomical regions of the brain involved in vision. These findings may explain, in part, the many recently reported neuro-ophthalmic manifestations of SARS-CoV-2infection in COVID-19 affected patients.

scholarly journals Fungal colonization of the brain: anatomopathological aspects of neurological cryptococcosis

2015 ◽  
Vol 87 (2 suppl) ◽  
pp. 1293-1309 ◽  
Author(s):  
ANA CAROLINE COLOMBO ◽  
MARCIO L. RODRIGUES
Keyword(s):  
Basic Research ◽  
Fungal Colonization ◽  
Brain Cells ◽  
Research Activity ◽  
Brain Infection ◽  
Clinical Syndromes ◽  
The Central Nervous System ◽  
Therapeutic Tools ◽  
Near Future ◽  
The Brain

Brain infection by the fungus Cryptococcus neoformans results in an estimated 500,000 human deaths per annum. Colonization of the central nervous system (CNS) by C. neoformans causes different clinical syndromes that involve interaction of a number of fungal components with distinct brain cells. In this manuscript, our literature review confirmed the notion that the Cryptococcus field is expanding rapidly, but also suggested that studies on neuropathogenesis still represent a small fraction of basic research activity in the field. We therefore discussed anatomical and physiological aspects of the brain during infection by C. neoformans, in addition to mechanisms by which brain resident cells interact with the fungus. This review suggests that multiple efforts are necessary to improve the knowledge on how C. neoformans affects brain cells, in order to enable the generation of new therapeutic tools in a near future.

scholarly journals ACE2, angiotensin 1-7 and skeletal muscle: review in the era of COVID-19

2020 ◽  
Vol 134 (22) ◽  
pp. 3047-3062
Author(s):  
Koichi Yamamoto ◽  
Hikari Takeshita ◽  
Hiromi Rakugi
Keyword(s):  
Skeletal Muscle ◽  
Transmembrane Protein ◽  
Renin Angiotensin System ◽  
Protective Role ◽  
Potential Contribution ◽  
Angiotensin Converting Enzyme 2 ◽  
Multiple Organs ◽  
Potential Association ◽  
Entry Receptor

Abstract Angiotensin converting enzyme-2 (ACE2) is a multifunctional transmembrane protein recently recognised as the entry receptor of the virus causing COVID-19. In the renin–angiotensin system (RAS), ACE2 cleaves angiotensin II (Ang II) into angiotensin 1-7 (Ang 1-7), which is considered to exert cellular responses to counteract the activation of the RAS primarily through a receptor, Mas, in multiple organs including skeletal muscle. Previous studies have provided abundant evidence suggesting that Ang 1-7 modulates multiple signalling pathways leading to protection from pathological muscle remodelling and muscle insulin resistance. In contrast, there is relatively little evidence to support the protective role of ACE2 in skeletal muscle. The potential contribution of endogenous ACE2 to the regulation of Ang 1-7-mediated protection of these muscle pathologies is discussed in this review. Recent studies have suggested that ACE2 protects against ageing-associated muscle wasting (sarcopenia) through its function to modulate molecules outside of the RAS. Thus, the potential association of sarcopenia with ACE2 and the associated molecules outside of RAS is also presented herein. Further, we introduce the transcriptional regulation of muscle ACE2 by drugs or exercise, and briefly discuss the potential role of ACE2 in the development of COVID-19.

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