A prenylated dsRNA sensor protects against severe COVID-19.

Inherited genetic factors can influence the severity of COVID-19, but the molecular explanation underpinning a genetic association is often unclear. Intracellular antiviral defenses can inhibit the replication of viruses and reduce disease severity. To better understand the antiviral defenses relevant to COVID-19, we used interferon-stimulated gene (ISG) expression screening to reveal that 2'-5'-oligoadenylate synthetase 1 (OAS1), through ribonuclease L, potently inhibits severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We show that a common splice-acceptor single-nucleotide polymorphism (Rs10774671) governs whether patients express prenylated OAS1 isoforms that are membrane-associated and sense-specific regions of SARS-CoV-2 RNAs or if they only express cytosolic, nonprenylated OAS1 that does not efficiently detect SARS-CoV-2. In hospitalized patients, expression of prenylated OAS1 was associated with protection from severe COVID-19, suggesting that this antiviral defense is a major component of a protective antiviral response.

In Vitro Models for Studying Entry, Tissue Tropism, and Therapeutic Approaches of Highly Pathogenic Coronaviruses.

Coronaviruses (CoVs) are enveloped nonsegmented positive-sense RNA viruses belonging to the family Coronaviridae that contain the largest genome among RNA viruses. Their genome encodes 4 major structural proteins, and among them, the Spike (S) protein plays a crucial role in determining the viral tropism. It mediates viral attachment to the host cell, fusion to the membranes, and cell entry using cellular proteases as activators. Several in vitro models have been developed to study the CoVs entry, pathogenesis, and possible therapeutic approaches. This article is aimed at summarizing the current knowledge about the use of relevant methodologies and cell lines permissive for CoV life cycle studies. The synthesis of this information can be useful for setting up specific experimental procedures. We also discuss different strategies for inhibiting the binding of the S protein to the cell receptors and the fusion process which may offer opportunities for therapeutic intervention.

Environmental pollution and COVID-19: the molecular terms and predominant disease outcomes of their sweetheart agreement.

As the Coronavirus situation (COVID-19) continues to evolve, many questions concerning the factors relating to the diffusion and severity of the disease remain unanswered.Whilst opinions regarding the weight of evidence for these risk factors, and the studies published so far are often inconclusive or offer contrasting results, the role of comorbidities in the risk of serious adverse outcomes in patients affected with COVID-19 appears to be evident since the outset. Hypertension, diabetes, and obesity are under discussion as important factors affecting the severity of disease. Air pollution has been considered to play a role in the diffusion of the virus, in the propagation of the contagion, in the severity of symptoms, and in the poor prognosis. Accumulating evidence supports the hypothesis that environmental particulate matter (PM) can trigger inflammatory responses at molecular, cellular, and organ levels, sustaining respiratory, cardiovascular, and dysmetabolic diseases.To better understand the intricate relationships among pre-existing conditions, PM, and viral infection, we examined the response at the molecular level of T47D human breast adenocarcinoma cells exposed to different fractions of PM. T47D cells express several receptors, including the aryl hydrocarbon receptor (AhR), and ACE2, the main - but not the only - receptor for SARS-CoV-2 entry.PM samples were collected in an urban background site located in the Northern area of the City of Bologna (Emilia-Romagna Region, Northern Italy) during winter 2013. T47D cells were exposed to organic or aqueous (inorganic) extracts at the final concentration of 8 m3 for a 4-hour duration. Both the concentration and the exposure time were chosen to resemble an average outdoor exposure. RNA was extracted from cells, purified and hybridised on 66k microarray slides from Agilent.The lists of differentially expressed genes in PM organic extracts were evaluated by using Metacore, and an enrichment analysis was performed to identify pathways maps, process networks, and disease by biomarkers altered after T47D treatment.The analysis of the modulated genes gave evidence for the involvement of PM in dysmetabolic diseases, including diabetes and obesity, and hypertension through the activation of the aryl hydrocarbon receptor (AhR) canonical pathway.On the basis of current knowledge, existing data, and exploratory experimental evidence, we tease out the likely molecular interplay that can ultimately tip the disease outcome into severity. Looking beyond ACE2, several additional key markers are identified. Disruption of these targets worsens pre-existing conditions and/or exacerbates the adverse effects induced by SARS-CoV-2 infection. Whilst appropriately designed, epidemiological studies are very much needed to investigate these associations based on our hypothesis of investigation, by reviewing recent experimental and epidemiological evidence, here we speculate and provide new insights on the possible role of environmental pollution in the exacerbation of effects by SARS-CoV-2 and other respiratory viruses. This work is intended to assist in the development of appropriate investigative approaches to protect public health.

Zoonotic evolution and implications of microbiome in viral transmission and infection.

The outbreak and spread of new strains of coronavirus (SARS-CoV-2) remain a global threat with increasing cases in affected countries. The evolutionary tree of SARS-CoV-2 revealed that Porcine Reproductive and Respiratory Syndrome virus 2, which belongs to the Beta arterivirus genus from the Arteriviridae family is possibly the most ancient ancestral origin of SARS-CoV-2 and other Coronaviridae. This review focuses on phylogenomic distribution and evolutionary lineage of zoonotic viral cross-species transmission of the Coronaviridae family and the implications of bat microbiome in zoonotic viral transmission and infection. The review also casts light on the role of the human microbiome in predicting and controlling viral infections. The significance of microbiome-mediated interventions in the treatment of viral infections is also discussed. Finally, the importance of synthetic viruses in the study of viral evolution and transmission is highlighted.

[Neurological damage linked to coronaviruses : SARS-CoV-2 and other human coronaviruses]. / Les atteintes neurologiques liées au SARS-CoV-2 et autres coronavirus humains.

The recent emergence of a new coronavirus, SARS-CoV-2, responsible for COVID-19, is a new warning of the risk to public health represented by viral zoonoses and in particular by coronaviruses. Mainly described as being able to infect the upper and lower respiratory tract, coronaviruses can also infect the central and peripheral nervous systems as many other respiratory viruses, such as influenza or respiratory syncytial virus. Viral infections of the nervous system are a major public health concern as they can cause devastating illnesses up to death, especially when they occur in the elderly, who are more susceptible to these infections. Knowledge concerning the pathophysiology of recently emerging coronaviruses (MERS-CoV, SARS-CoV and SARS-CoV-2) and how they reach the central nervous system are very sketchy and the work in progress aims in particular to better understand their biology and the mechanisms associated with neurological damage. In this review we will discuss the current state of knowledge on the neurotropism of human coronaviruses and the associated mechanisms by developing in particular the latest data concerning SARS-CoV-2.

TITLE: Les atteintes neurologiques liées au SARS-CoV-2 et autres coronavirus humains. ABSTRACT: L'émergence récente d'un nouveau coronavirus, le SARS-CoV-2, responsable de la maladie appelée COVID-19, est un nouvel avertissement du risque pour la santé publique représenté par les zoonoses virales et notamment par les coronavirus. Principalement connus pour leur capacité à infecter les voies respiratoires supérieures et inférieures, les coronavirus peuvent également affecter le système nerveux central et périphérique, comme c'est le cas pour de nombreux virus respiratoires, tels que les virus influenza ou le virus respiratoire syncytial. Les infections du système nerveux sont un problème important de santé publique car elles peuvent provoquer des atteintes dévastatrices allant jusqu'au décès du patient, en particulier lorsqu'elles surviennent chez les personnes fragilisées ou âgées plus sensibles à ce type d'infection. Les connaissances de la physiopathologie des infections par les coronavirus émergents (MERS-CoV, SARS-CoV et SARS-CoV-2) et leurs moyens d'accéder au système nerveux central sont, pour l'heure, très sommaires. Les travaux en cours visent notamment à mieux appréhender les mécanismes associés aux atteintes neurologiques observées. Dans cette revue nous aborderons l'état des connaissances actuelles sur le neurotropisme des coronavirus humains et les mécanismes associés en développant tout particulièrement les dernières données concernant le SARS-CoV-2.

Roles of flavonoids against coronavirus infection.

In terms of public health, the 21st century has been characterized by coronavirus pandemics: in 2002-03 the virus SARS-CoV caused SARS; in 2012 MERS-CoV emerged and in 2019 a new human betacoronavirus strain, called SARS-CoV-2, caused the unprecedented COVID-19 outbreak. During the course of the current epidemic, medical challenges to save lives and scientific research aimed to reveal the genetic evolution and the biochemistry of the vital cycle of the new pathogen could lead to new preventive and therapeutic strategies against SARS-CoV-2. Up to now, there is no cure for COVID-19 and waiting for an efficacious vaccine, the development of "savage" protocols, based on "old" anti-inflammatory and anti-viral drugs represents a valid and alternative therapeutic approach. As an alternative or additional therapeutic/preventive option, different in silico and in vitro studies demonstrated that small natural molecules, belonging to polyphenol family, can interfere with various stages of coronavirus entry and replication cycle. Here, we reviewed the capacity of well-known (e.g. quercetin, baicalin, luteolin, hesperetin, gallocatechin gallate, epigallocatechin gallate) and uncommon (e.g. scutellarein, amentoflavone, papyriflavonol A) flavonoids, secondary metabolites widely present in plant tissues with antioxidant and anti-microbial functions, to inhibit key proteins involved in coronavirus infective cycle, such as PLpro, 3CLpro, NTPase/helicase. Due to their pleiotropic activities and lack of systemic toxicity, flavonoids and their derivative may represent target compounds to be tested in future clinical trials to enrich the drug arsenal against coronavirus infections.

A literature review of 2019 novel coronavirus (SARS-CoV2) infection in neonates and children.

At the time of writing, there are already millions of documented infections worldwide by the novel coronavirus 2019 (2019-nCoV or severe acute respiratory syndrome coronavirus 2 (SARS-CoV2)), with hundreds of thousands of deaths. The great majority of fatal events have been recorded in adults older than 70 years; of them, a large proportion had comorbidities. Since data regarding the epidemiologic and clinical characteristics in neonates and children developing coronavirus disease 2019 (COVID-19) are scarce and originate mainly from one country (China), we reviewed all the current literature from 1 December 2019 to 7 May 2020 to provide useful information about SARS-CoV2 viral biology, epidemiology, diagnosis, clinical features, treatment, prevention, and hospital organization for clinicians dealing with this selected population. IMPACT: Children usually develop a mild form of COVID-19, rarely requiring high-intensity medical treatment in pediatric intensive care unit. Vertical transmission is unlikely, but not completely excluded. Children with confirmed or suspected COVID-19 must be isolated and healthcare workers should wear appropriate protective equipment. Some clinical features (higher incidence of fever, vomiting and diarrhea, and a longer incubation period) are more common in children than in adults, as well as some radiologic aspects (more patchy shadow opacities on CT scan images than ground-glass opacities). Supportive and symptomatic treatments (oxygen therapy and antibiotics for preventing/treating bacterial coinfections) are recommended in these patients.

The neurology of COVID-19 revisited: A proposal from the Environmental Neurology Specialty Group of the World Federation of Neurology to implement international neurological registries.

A comprehensive review of the neurological disorders reported during the current COVID-19 pandemic demonstrates that infection with SARS-CoV-2 affects the central nervous system (CNS), the peripheral nervous system (PNS) and the muscle. CNS manifestations include: headache and decreased responsiveness considered initial indicators of potential neurological involvement; anosmia, hyposmia, hypogeusia, and dysgeusia are frequent early symptoms of coronavirus infection. Respiratory failure, the lethal manifestation of COVID-19, responsible for 264,679 deaths worldwide, is probably neurogenic in origin and may result from the viral invasion of cranial nerve I, progressing into rhinencephalon and brainstem respiratory centers. Cerebrovascular disease, in particular large-vessel ischemic strokes, and less frequently cerebral venous thrombosis, intracerebral hemorrhage and subarachnoid hemorrhage, usually occur as part of a thrombotic state induced by viral attachment to ACE2 receptors in endothelium causing widespread endotheliitis, coagulopathy, arterial and venous thromboses. Acute hemorrhagic necrotizing encephalopathy is associated to the cytokine storm. A frontal hypoperfusion syndrome has been identified. There are isolated reports of seizures, encephalopathy, meningitis, encephalitis, and myelitis. The neurological diseases affecting the PNS and muscle in COVID-19 are less frequent and include Guillain-Barré syndrome; Miller Fisher syndrome; polyneuritis cranialis; and rare instances of viral myopathy with rhabdomyolysis. The main conclusion of this review is the pressing need to define the neurology of COVID-19, its frequency, manifestations, neuropathology and pathogenesis. On behalf of the World Federation of Neurology we invite national and regional neurological associations to create local databases to report cases with neurological manifestations observed during the on-going pandemic. International neuroepidemiological collaboration may help define the natural history of this worldwide problem.