scholarly journals Anosmia in COVID-19: Underlying Mechanisms and Assessment of an Olfactory Route to Brain Infection

2020 ◽  
pp. 107385842095690 ◽  
Author(s):  
Rafal Butowt ◽  
Christopher S. von Bartheld
Keyword(s):  
Olfactory Epithelium ◽  
Molecular Mechanisms ◽  
Large Fraction ◽  
Current Evidence ◽  
The Novel ◽  
Brain Infection ◽  
Sustentacular Cells ◽  
Underlying Mechanisms ◽  
Novel Coronavirus ◽  
Taste Dysfunction

In recent months it has emerged that the novel coronavirus—responsible for the COVID-19 pandemic—causes reduction of smell and taste in a large fraction of patients. The chemosensory deficits are often the earliest, and sometimes the only signs in otherwise asymptomatic carriers of the SARS-CoV-2 virus. The reasons for the surprisingly early and specific chemosensory dysfunction in COVID-19 are now beginning to be elucidated. In this hypothesis review, we discuss implications of the recent finding that the prevalence of smell and taste dysfunction in COVID-19 patients differs between populations, possibly because of differences in the spike protein of different virus strains or because of differences in the host proteins that enable virus entry, thus modifying infectivity. We review recent progress in defining underlying cellular and molecular mechanisms of the virus-induced anosmia, with a focus on the emerging crucial role of sustentacular cells in the olfactory epithelium. We critically examine the current evidence whether and how the SARS-CoV-2 virus can follow a route from the olfactory epithelium in the nose to the brain to achieve brain infection, and we discuss the prospects for using the smell and taste dysfunctions seen in COVID-19 as an early and rapid diagnostic screening tool.

scholarly journals COVID-19-related anosmia is associated with viral persistence and inflammation in human olfactory epithelium and brain infection in hamsters

2021 ◽  
pp. eabf8396
Author(s):  
Guilherme Dias de Melo ◽  
Françoise Lazarini ◽  
Sylvain Levallois ◽  
Charlotte Hautefort ◽  
Vincent Michel ◽  
...  
Keyword(s):  
Olfactory Epithelium ◽  
Cell Types ◽  
Brain Infection ◽  
Olfactory Neuroepithelium ◽  
Optimal Medical Management ◽  
Infected Cells ◽  
Multiple Cell ◽  
Lung Pathogenesis ◽  
Taste Dysfunction

Whereas recent investigations have revealed viral, inflammatory and vascular factors involved in SARS-CoV-2 lung pathogenesis, the pathophysiology of neurological disorders in COVID-19 remains poorly understood. Olfactory and taste dysfunction are common in COVID-19, especially in mildly symptomatic patients. Here, we conducted a virologic, molecular, and cellular study of the olfactory neuroepithelium of seven patients with COVID-19 presenting with acute loss of smell. We report evidence that the olfactory neuroepithelium may be a major site of SARS-CoV2 infection with multiple cell types, including olfactory sensory neurons, support cells, and immune cells, becoming infected. SARS-CoV-2 replication in the olfactory neuroepithelium was associated with local inflammation. Furthermore, we showed that SARS-CoV-2 induced acute anosmia and ageusia in golden Syrian hamsters, lasting as long as the virus remained in the olfactory epithelium and the olfactory bulb. Finally, olfactory mucosa sampling from patients showing long-term persistence of COVID-19-associated anosmia revealed the presence of virus transcripts and of SARS-CoV-2-infected cells, together with protracted inflammation. SARS-CoV-2 persistence and associated inflammation in the olfactory neuroepithelium may account for prolonged or relapsing symptoms of COVID-19, such as loss of smell, which should be considered for optimal medical management of this disease.

scholarly journals Structural basis for receptor recognition by the novel coronavirus from Wuhan

2020 ◽  
Author(s):  
Jian Shang ◽  
Gang Ye ◽  
Ke Shi ◽  
Yushun Wan ◽  
Chuming Luo ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Structural Changes ◽  
Molecular Mechanisms ◽  
Intervention Strategies ◽  
Structural Basis ◽  
The Novel ◽  
Recognition Mechanism ◽  
Future Evolution ◽  
Receptor Recognition ◽  
Novel Coronavirus

Abstract A novel SARS-like coronavirus (2019-nCoV) recently emerged from Wuhan, China and is quickly spreading in humans. A key to tackling this epidemic is to understand the virus’s receptor recognition mechanism, which regulates its infection, pathogenesis, and host range. 2019-nCoV and SARS-CoV recognize the same host receptor ACE2. Here we determined the crystal structure of 2019-nCoV receptor-binding domain (RBD) (engineered to facilitate crystallization) in complex of human ACE2.Compared with SARS-CoV, an ACE2-binding ridge in 2019-nCoV RBD takes more compact conformations, causing structural changes at the RBD/ACE2 interface. Adaptive to these structural changes, several mutations in 2019-nCoV RBD enhance ACE2- binding affinity, contributing to the high infectivity of 2019-CoV. These mutations also reveal the molecular mechanisms of the animal-to-human transmission of 2019-nCoV. Alarmingly, a single N439R mutation in 2019-nCoV RBD further enhances its ACE2- binding affinity, indicating possible future evolution of 2019-nCoV in humans. This study sheds light on the epidemiology and evolution of 2019-nCoV, and provides guidance for intervention strategies targeting receptor recognition by 2019-nCoV.

scholarly journals Time from Symptom Onset to Hospitalisation of Coronavirus Disease 2019 (COVID-19) Cases: Implications for the Proportion of Transmissions from Infectors with Few Symptoms

2020 ◽  
Vol 9 (5) ◽  
pp. 1297 ◽  
Author(s):  
Robin N. Thompson ◽  
Francesca A. Lovell-Read ◽  
Uri Obolski
Keyword(s):  
Basic Reproduction Number ◽  
Symptom Onset ◽  
Reproduction Number ◽  
Wide Spectrum ◽  
Control Measures ◽  
Current Evidence ◽  
The Novel ◽  
Novel Coronavirus ◽  
The Basic Reproduction Number

Interventions targeting symptomatic hosts and their contacts were successful in bringing the 2003 SARS pandemic under control. In contrast, the COVID-19 pandemic has been harder to contain, partly because of its wide spectrum of symptoms in infectious hosts. Current evidence suggests that individuals can transmit the novel coronavirus while displaying few symptoms. Here, we show that the proportion of infections arising from hosts with few symptoms at the start of an outbreak can, in combination with the basic reproduction number, indicate whether or not interventions targeting symptomatic hosts are likely to be effective. However, as an outbreak continues, the proportion of infections arising from hosts with few symptoms changes in response to control measures. A high proportion of infections from hosts with few symptoms after the initial stages of an outbreak is only problematic if the rate of new infections remains high. Otherwise, it can simply indicate that symptomatic transmissions are being prevented successfully. This should be considered when interpreting estimates of the extent of transmission from hosts with few COVID-19 symptoms.

scholarly journals Prospective: Evolution of Chinese Medicine to Treat COVID-19 Patients in China

2021 ◽  
Vol 11 ◽  
Author(s):  
Jieya Wu ◽  
Baoguo Sun ◽  
Li Hou ◽  
Fulan Guan ◽  
Liyuan Wang ◽  
...  
Keyword(s):  
Chinese Medicine ◽  
Renin Angiotensin System ◽  
Chinese Government ◽  
The Novel ◽  
Angiotensin System ◽  
Medical Needs ◽  
Anti Inflammatory ◽  
Underlying Mechanisms ◽  
Novel Coronavirus ◽  
The Individual

During the outbreak of the novel coronavirus disease (COVID-19), the Chinese government took a series of public health measures to tackle the outbreak and recommended six traditional Chinese medicine (TCM) evolved formulas, collectively referred to as “3-drugs-3-formulas”, for the treatment. In this prospective article, we will discuss how these six formulas evolved from TCM and what their underlying mechanisms of actions may be by evaluating the historical usage of the component formulas, the potential targeted pathways for the individual herbs used by STAR (signal transduction activity response) database from our laboratory, and the pathogenesis of COVID-19. Five of the six recommended formulas are administered orally, while the sixth is taken as an injection. Five classic categories of herbs in the six formulas including “Qing-Re”, “Qu-Shi”, “Huo-Xue”, “Bu-Yi” and “Xing-Qi” herbs are used based on different stages of disease. All five oral formulas build upon the core formula Maxingshigan Decoction (MD) which has anti-inflammatory and perhaps antiviral actions. While MD can have some desired effects, it may not be sufficient to treat COVID-19 on its own; consequently, complementary classic formulas and/or herbs have been added to potentiate each recommended formula’s anti-inflammatory, and perhaps anti-renin-angiotensin system (RAS)-mediated bradykinin storm (RBS) and antiviral effects to address the unique medical needs for different stages of COVID-19. The key actions of these formulas are likely to control systemic inflammation and/or RBS. The usage of Chinese medicine in the six formulas is consistent with the pathogenesis of COVID-19. Thus, an integrative systems biology approach—combining botanical treatments of conventional antiviral, anti-inflammatory or anti-RBS drugs to treat COVID-19 and its complications – should be explored.

scholarly journals The Cellular basis of loss of smell in 2019-nCoV-infected individuals

2020 ◽  
Author(s):  
Krishan Gupta ◽  
Sanjay Kumar Mohanty ◽  
Aayushi Mittal ◽  
Siddhant Kalra ◽  
Suvendu Kumar ◽  
...  
Keyword(s):  
Olfactory Epithelium ◽  
Viral Entry ◽  
Mammalian Species ◽  
Expression Patterns ◽  
Cell Types ◽  
Cellular Basis ◽  
Protein Protein Interaction ◽  
Sustentacular Cells ◽  
Novel Coronavirus ◽  
Cell Expression

Abstract A prominent clinical symptom of 2019-novel coronavirus (nCoV) infection is hyposmia/anosmia (decrease or loss of sense of smell), along with general symptoms such as fatigue, shortness of breath, fever and cough. The identity of the cell lineages that underpin the infection-associated loss of olfaction could be critical for the clinical management of 2019-nCoV-infected individuals. Recent research has confirmed the role of angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) as key host-specific cellular moieties responsible for the cellular entry of the virus. Accordingly, the ongoing medical examinations and the autopsy reports of the deceased individuals indicate that organs/tissues with high expression levels of ACE2, TMPRSS2 and other putative viral entry-associated genes are most vulnerable to the infection. We studied if anosmia in 2019-nCoV-infected individuals can be explained by the expression patterns associated with these host-specific moieties across the known olfactory epithelial cell types, identified from a recently published single-cell expression study. Our findings underscore selective expression of these viral entry-associated genes in a subset of sustentacular cells (SUSs), Bowman’s gland cells (BGCs) and stem cells of the olfactory epithelium. Co-expression analysis of ACE2 and TMPRSS2 and protein–protein interaction among the host and viral proteins elected regulatory cytoskeleton protein-enriched SUSs as the most vulnerable cell type of the olfactory epithelium. Furthermore, expression, structural and docking analyses of ACE2 revealed the potential risk of olfactory dysfunction in four additional mammalian species, revealing an evolutionarily conserved infection susceptibility. In summary, our findings provide a plausible cellular basis for the loss of smell in 2019-nCoV-infected patients.

scholarly journals Molecular mechanisms of the novel coronavirus SARS-CoV-2 and potential anti-COVID19 pharmacological targets since the outbreak of the pandemic

2020 ◽  
Vol 146 ◽  
pp. 111805
Author(s):  
Dimitrios Vlachakis ◽  
Eleni Papakonstantinou ◽  
Thanasis Mitsis ◽  
Katerina Pierouli ◽  
Io Diakou ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
The Novel ◽  
Pharmacological Targets ◽  
Novel Coronavirus

scholarly journals Inflammation Triggered by SARS-CoV-2 and ACE2 Augment Drives Multiple Organ Failure of Severe COVID-19: Molecular Mechanisms and Implications

Inflammation ◽  
2020 ◽  
Author(s):  
Masae Iwasaki ◽  
Junichi Saito ◽  
Hailin Zhao ◽  
Atsuhiro Sakamoto ◽  
Kazuyoshi Hirota ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Renin Angiotensin System ◽  
Multiple Organ ◽  
Host Cells ◽  
Organ Injury ◽  
Current Evidence ◽  
Necrosis Factor Alpha ◽  
Angiotensin Converting Enzyme 2 ◽  
Underlying Mechanisms

Abstract The widespread occurrence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to a pandemic of coronavirus disease 2019 (COVID-19). The S spike protein of SARS-CoV-2 binds with angiotensin-converting enzyme 2 (ACE2) as a functional “receptor” and then enters into host cells to replicate and damage host cells and organs. ACE2 plays a pivotal role in the inflammation, and its downregulation may aggravate COVID-19 via the renin-angiotensin system, including by promoting pathological changes in lung injury and involving inflammatory responses. Severe patients of COVID-19 often develop acute respiratory distress syndrome and multiple organ dysfunction/failure with high mortality that may be closely related to the hyper-proinflammatory status called the “cytokine storm.” Massive cytokines including interleukin-6, nuclear factor kappa B (NFκB), and tumor necrosis factor alpha (TNFα) released from SARS-CoV-2-infected macrophages and monocytes lead inflammation-derived injurious cascades causing multi-organ injury/failure. This review summarizes the current evidence and understanding of the underlying mechanisms of SARS-CoV-2, ACE2 and inflammation co-mediated multi-organ injury or failure in COVID-19 patients.

scholarly journals COVID-19 Therapy: the Role of Antirheumatic Drugs

2021 ◽  
Vol 66 (7-8) ◽  
pp. 83-89
Author(s):  
M. A. Litvinova ◽  
N. V. Muravyeva ◽  
B. S. Belov
Keyword(s):  
The Novel ◽  
Huge Amount ◽  
Close Attention ◽  
Antirheumatic Drugs ◽  
Coronavirus Infection ◽  
Underlying Mechanisms ◽  
Novel Coronavirus ◽  
Contradictory Data ◽  
Selection Of

Currently, the close attention of the medical and international community is still riveted on the novel coronavirus infection, which caused the pandemic in 2020. Understanding the underlying mechanisms of coronavirus disease-2019 (COVID-19) made it possible to move from the empirical selection of therapy, which was observed at the beginning of the pandemic, to the pathogenetically justified prescription of drugs, including glucocorticoids, anticoagulants, as well as some antirheumatic drugs. However, despite the huge amount of scientific and clinical material accumulated over 1.5 years, the interest in this problem does not wane both due to the existence of a number of unresolved issues, and due to the constant emergence of new (often contradictory) data.

scholarly journals Molecular interaction and inhibition of SARS-CoV-2 binding to the ACE2 receptor

2020 ◽  
Author(s):  
Jinsung Yang ◽  
Simon Petitjean ◽  
Sylvie Derclaye ◽  
Melanie Koehler ◽  
Qingrong Zhang ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Binding Pocket ◽  
Host Cells ◽  
The Novel ◽  
Angiotensin Converting Enzyme 2 ◽  
Force Microscopy ◽  
Binding Interface ◽  
Atomic Force ◽  
Viral Glycoproteins ◽  
Novel Coronavirus

Abstract Study of virus entry into cells is of critical importance for a better understanding of the interactions established between the viral glycoproteins and their receptors at the cell surface and could help to develop novel antiviral strategies. The novel coronavirus (SARS-CoV-2) entry into host cells is mediated by the transmembrane spike glycoprotein (S-glycoprotein) and the angiotensin-converting enzyme 2 (ACE2) has been identified as a cellular receptor. Here, we used atomic force microscopy to investigate the molecular mechanisms by which the S- glycoprotein binds to the ACE2 receptor. We demonstrated, both on model surfaces and on living cells, that the receptor binding domain (RBD) serves as a binding interface within the S- glycoprotein with the ACE2 receptor and we extracted the kinetic and thermodynamic properties of this binding pocket. Altogether, these results give a dynamic picture of the established interaction in physiologically relevant conditions. Finally, we identified and tested several binding inhibitor peptides targeting the virus early attachment stages, offering new perspectives in the treatment of the SARS-CoV-2 infection.

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