Largest RNA Virus Research Articles

Evolutionary deletions within the SARS-CoV-2 genome as signature trends for virus fitness and adaptation.

Coronaviruses are large RNA viruses that can infect and spread among humans and animals. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for coronavirus disease 2019, has evolved since its first detection in December 2019. Deletions are a common occurrence in SARS-CoV-2 evolution, particularly in specific genomic sites, and may be associated with the emergence of highly competent lineages. While deletions typically have a negative impact on viral fitness, some persist and become fixed in viral populations, indicating that they may confer advantageous benefits for the virus's adaptive evolution. This work presents a literature review and data analysis on structural losses in the SARS-CoV-2 genome and the potential relevance of specific signatures for enhanced viral fitness and spread.

Extensive Recombination-driven Coronavirus Diversification Expands the Pool of Potential Pandemic Pathogens.

The ongoing SARS-CoV-2 pandemic is the third zoonotic coronavirus identified in the last 20 years. Enzootic and epizootic coronaviruses of diverse lineages also pose a significant threat to livestock, as most recently observed for virulent strains of porcine epidemic diarrhea virus (PEDV) and swine acute diarrhea-associated coronavirus (SADS-CoV). Unique to RNA viruses, coronaviruses encode a proofreading exonuclease (ExoN) that lowers point mutation rates to increase the viability of large RNA virus genomes, which comes with the cost of limiting virus adaptation via point mutation. This limitation can be overcome by high rates of recombination that facilitate rapid increases in genetic diversification. To compare the dynamics of recombination between related sequences, we developed an open-source computational workflow (IDPlot) that bundles nucleotide identity, recombination, and phylogenetic analysis into a single pipeline. We analyzed recombination dynamics among three groups of coronaviruses with noteworthy impacts on human health and agriculture: SARSr-CoV, Betacoronavirus-1, and SADSr-CoV. We found that all three groups undergo recombination with highly diverged viruses from undersampled or unsampled lineages, including in typically highly conserved regions of the genome. In several cases, no parental origin of recombinant regions could be found in genetic databases, demonstrating our shallow characterization of coronavirus diversity and expanding the genetic pool that may contribute to future zoonotic events. Our results also illustrate the limitations of current sampling approaches for anticipating zoonotic threats to human and animal health.

SARS-CoV-2 genetic material is removed during municipal wastewater treatment and is undetectable after advanced treatment

The aim of this study was to establish whether SARS-CoV-2 genetic material is detectable after municipal wastewater treatment and to verify its expected removal from purified water that is reclaimed for potable reuse. Viral loads of SARS-CoV-2 (N1 and N2 genes) were monitored in raw influent wastewater (sewage) entering a water reclamation facility and in subsequent advanced treatment. Despite the large viral RNA load in raw sewage during peak COVID-19 outbreaks, substantial amounts of SARS-CoV-2 genetic material were removed during the conventional wastewater treatment process. Further, SARS-CoV-2 genetic material was undetectable after advanced purification. This confirms that potable reuse is resilient against high viral loads which are expected results given the advanced degree of wastewater and water treatment. Findings from this study may enhance public perception of the safety of potable water reuse; however, it should also be noted that studies to date worldwide indicate no evidence of SARS-CoV-2 transmission via water, and the CDC does not consider fecal waste or wastewaters as a source of exposure.

A second type of N7-guanine RNA cap methyltransferase in an unusual locus of a large RNA virus genome.

The order Nidovirales is a diverse group of (+)RNA viruses, with a common genome organization and conserved set of replicative and editing enzymes. In particular, RNA methyltransferases play a central role in mRNA stability and immune escape. However, their presence and distribution in different Nidovirales families is not homogeneous. In Coronaviridae, the best characterized family, two distinct methytransferases perform methylation of the N7-guanine and 2'-OH of the RNA-cap to generate a cap-1 structure (m7GpppNm). The genes of both of these enzymes are located in the ORF1b genomic region. While 2'-O-MTases can be identified for most other families based on conservation of both sequence motifs and genetic loci, identification of the N7-guanine methyltransferase has proved more challenging. Recently, we identified a putative N7-MTase domain in the ORF1a region (N7-MT-1a) of certain members of the large genome Tobaniviridae family. Here, we demonstrate that this domain indeed harbors N7-specific methyltransferase activity. We present its structure as the first N7-specific Rossmann-fold (RF) MTase identified for (+)RNA viruses, making it remarkably different from that of the known Coronaviridae ORF1b N7-MTase gene. We discuss the evolutionary implications of such an appearance in this unexpected location in the genome, which introduces a split-off in the classification of Tobaniviridae.

COVID-19 pandemic: disease impact on nervous system, cognitive functioning and mental health

Introduction and purpose:COVID-19, as an unknown disease until 2019, has posed and continues to pose a great challenge to the world of science and the people facing it. The purpose of this article is to present the possible consequences of experiencing COVID-19 disease and the pandemic itself in light of mental health and the organism functioning in the cognitive area, taking into account the impact of COVID-19 on the nervous system.State of knowledge (brief description):Coronaviruses are enveloped, positive single-stranded large RNA viruses. COVID-19 is a disease caused by the SARS-CoV-2 virus – its first case was reported in 2019 in Wuhan, China. Human coronaviruses can exhibit neuroinvasive, neurotropic and neurovirulent, SARS-CoV-2 also. In addition to symptoms and complications in the respiratory system, symptoms and complications are also encountered in the nervous system area; cognitive functioning may also be impaired. The pandemic as a phenomenon in itself and the outbreak of COVID-19 can carry very serious consequences from the mental health field. Among these are the problem of social isolation and its consequences or the impact of the disease and pandemic on well-being. Unfortunately, the time that has elapsed since the first cases of the disease and the amount of research does not allow a clear determination of the complications and consequences of the pandemic, but certain trends and phenomena are regularly studied and described.Summary:Existing research and the state of the art strongly underscore that COVID-19 and its pandemic could impinge on the mental health of people around the world. Changes in the nervous system and cognitive functioning are also observed as a result of contracting COVID-19. Science currently has no clear answers as to how long certain complications will persist and exactly what their genesis is – further research is recommended to explain them as precisely as possible.

A highly specific N7-guanine RNA cap methyltransferase in an unusual locus of large RNA virus genome

A highly specific N7-guanine RNA cap methyltransferase in an unusual locus of large RNA virus genome

Host Cellular RNA Helicases Regulate SARS-CoV-2 Infection.

ABSTRACTSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has the largest RNA genome, approximately 30 kb, among RNA viruses. The DDX DEAD box RNA helicase is a multifunctional protein involved in all aspects of RNA metabolism. Therefore, host RNA helicases may regulate and maintain such a large viral RNA genome. In this study, I investigated the potential role of several host cellular RNA helicases in SARS-CoV-2 infection. Notably, DDX21 knockdown markedly accumulated intracellular viral RNA and viral production, as well as viral infectivity of SARS-CoV-2, indicating that DDX21 strongly restricts the SARS-CoV-2 infection. In addition, MOV10 RNA helicase also suppressed the SARS-CoV-2 infection. In contrast, DDX1, DDX5, and DDX6 RNA helicases were required for SARS-CoV-2 replication. Indeed, SARS-CoV-2 infection dispersed the P-body formation of DDX6 and MOV10 RNA helicases as well as XRN1 exonuclease, while the viral infection did not induce stress granule formation. Accordingly, the SARS-CoV-2 nucleocapsid (N) protein interacted with DDX1, DDX3, DDX5, DDX6, DDX21, and MOV10 and disrupted the P-body formation, suggesting that SARS-CoV-2 N hijacks DDX6 to carry out viral replication. Conversely, DDX21 and MOV10 restricted SARS-CoV-2 infection through an interaction of SARS-CoV-2 N with host cellular RNA helicases. Altogether, host cellular RNA helicases seem to regulate the SARS-CoV-2 infection.IMPORTANCE SARS-CoV-2 has a large RNA genome, of approximately 30 kb. To regulate and maintain such a large viral RNA genome, host RNA helicases may be involved in SARS-CoV-2 replication. In this study, I have demonstrated that DDX21 and MOV10 RNA helicases limit viral infection and replication. In contrast, DDX1, DDX5, and DDX6 are required for SARS-CoV-2 infection. Interestingly, SARS-CoV-2 infection disrupted P-body formation and attenuated or suppressed stress granule formation. Thus, SARS-CoV-2 seems to hijack host cellular RNA helicases to play a proviral role by facilitating viral infection and replication and by suppressing the host innate immune system.

Male Reproductive Tract Involvement and Sperm Parameters in SARS-CoV-2 Patients: A Systematic Review and Meta-Analysis.

There is a growing concern regarding the impact of SARS-CoV-2 infection on the male reproductive tract due to ACE2 receptor expression, however, its impact remains unclear. We performed this review to evaluate whether SARS-CoV-2 infection affects the male reproductive system. We conducted a search in the Embase, Scopus, and MEDLINE databases, adhering to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline. Eligible studies comprised articles reporting viral RNA presence in semen, sperm parameters, and orchitis or orchiepididymitis occurrence in SARS-CoV-2 patients. Observational studies' quality was determined using the Newcastle-Ottawa Scale (NOS). Case reports were assessed using the Joanna Briggs Institute (JBI)'s checklist. A total of 32 relevant articles were included. Viral RNA was found in 7% of infected patients' semen (95% CI, -0.01 to 0.15) from 3 studies. There were also only 7% of patients with orchitis or orchiepididymitis clinical manifestations (95% CI, 0.05-0.10). The semen volume and concentration were 2.34 mL (95% CI, 1.87-2.81) and 51.73 million/mL (95% CI, 31.60-71.85). The progressive and total motility percentages were 36.11% (95% CI, 28.87-43.35) and 43.07% (95% CI, 28.57-57.57), respectively. The morphology was 6.03% (95% CI, -1.05 to 13.10). There is a difference in semen volume between moderate and severe infections (MD, 0.52; 95% CI, 0.27-0.76; p<0.0001) and concentration between mild and moderate (MD, 18.74; 95% CI, 1.02-36.46; p=0.04), mild and severe (MD, 43.50; 95% CI, 13.86-73.14; p=0.004), as well as moderate and severe (MD, 22.25; 95% CI, 9.33-35.17; p=0.0007). SARS-CoV-2 infection may result in decreased sperm concentration in severe cases and the mechanism relates to potential reproductive tract inflammation. The absence of large viral RNA detection in the semen indicates a systemic effect, although this is largely unproven.

Can a Multi-Epitope Vaccine be a solution for COVID-19 pandemic?

COVID-19 virus, SARS-CoV-2 first reported from Wuhan City of Hubei Province of China became pandemic infectious disease of severe respiratory disorder. Globally 17.8 Cr population was effected within a short span of period leading to 38.6 L deaths. Coronoviruses are large enveloped RNA viruses of Coronaviridae. Coronavirus employs a complex gene expression and pathway system unique among RNA viruses. SARA-CoV-2 is reported to mutate and variants reported to have one specific mutation, D614G which is makes to spread faster. WHO is monitoring and assessing the evolution of SARS-CoV-2 and notified Variants of Concern (VOCs) and Variants of Interest (VOIs), in order to prioritise the activities globally on containing COVID-19 pandemic. Currently genetic lineages by GISAID, Nextstrain and Pango are in use to code variants detected and being labeled using letters of the Greek Alphabet, i.e., Alpha, Beta, Gamma and Delta etc. Presently 15 vaccines were developed based on the SARS-CoV-2 spike protein, of original Wuhan-hu-1 and being administered in different countries. Surveillance and monitoring of the genomic sequence of SARS-CoV-2 is being done on a priority as virus is mutating for development of effective vaccine or therapeutic measures. Only 0.8% of people in low-income countries have received a single dose out of 20.8% of the world population which is a big concern for vulnerable groups.

In silico Design of a Vaccine Candidate for SAR S-CoV-2 Based on Multiple T-cell and B-cell Epitopes.

Coronaviruses (2019-nCoV) are large single-stranded RNA viruses that usually cause respiratory infections with a crude lethality ratio of 3.8% and high levels of transmissibility. There is yet no applicable clinical evaluation to assess the efficacy of various therapeutic agents that have been suggested as investigational drugs against the viruses despite their respective supposed hypothetical claims due to their antiviral potentials. Moreover, the development of a safe and effective vaccine has been suggested as an intervention to control the 2019-nCoV pandemic. However, a major concern in the development of a 2019-nCoV vaccine is the possibility of stimulating a corresponding immune response without enhancing the induction of the disease and associated side effects. The present investigation was carried out by predicting the antigenicity of the primary sequences of 2019-nCoV structural proteins and identification of B-cell and T-cell epitopes through the Bepipred and PEPVAC servers, respectively. The peptides of the vaccine construct include the selected epitopes based on the VaxiJen score with a threshold of 1.0 and β-defensinas an adjuvant. The putative binding of the vaccine constructs to intracellular toll-like receptors (TLRs) was assessed through molecular docking analysis and molecular dynamics simulations. The selected epitopes for the final vaccine construct are DPNFKD, SPLSLN, and LELQDHNE as B-cell epitopes and EPKLGSLVV, NFKDQVILL, and SSRSSSRSR as T-cell epitopes. The molecular docking analysis showed the vaccine construct could have favorable interactions with TLRs as indicated by the negative values of the computed binding energies. The constructed immunogen based on the immune informatics study could be employed in the strategy to develop potential vaccine candidates against 2019-nCoV.

Mutation Rates, Mutation Frequencies, and Proofreading-Repair Activities in RNA Virus Genetics.

The error rate displayed during template copying to produce viral RNA progeny is a biologically relevant parameter of the replication complexes of viruses. It has consequences for virus–host interactions, and it represents the first step in the diversification of viruses in nature. Measurements during infections and with purified viral polymerases indicate that mutation rates for RNA viruses are in the range of 10−3 to 10−6 copying errors per nucleotide incorporated into the nascent RNA product. Although viruses are thought to exploit high error rates for adaptation to changing environments, some of them possess misincorporation correcting activities. One of them is a proofreading-repair 3′ to 5′ exonuclease present in coronaviruses that may decrease the error rate during replication. Here we review experimental evidence and models of information maintenance that explain why elevated mutation rates have been preserved during the evolution of RNA (and some DNA) viruses. The models also offer an interpretation of why error correction mechanisms have evolved to maintain the stability of genetic information carried out by large viral RNA genomes such as the coronaviruses.

A Mini Review Medicinal plants with Antiviral properties against SARS-CoV-2

Background: The aim of the present project is to provide basic knowledge about the treatment of Coronavirus via medicinal plants. Coronavirus (COVID-19, SARS-CoV, and MERS-CoV) as a viral pneumonia causative agent, infects thousands of people worldwide. There is currently no specific medicine or vaccine available and it is considered a threat to develop effective novel drug or anti-coronavirus vaccine treatment. However, natural compounds to treat coronaviruses are the most alternative and complementary therapies due to their diverse range of biological and therapeutic properties. Coronaviruses have large viral RNA Genomes and are single-stranded positive-sense RNA viruses. The nsp10/nsp16 protein is an important target because it is essential for the virus to replicate, the papain-like protease (Nsp3), the main protease (Nsp5), the primary RNA-dependent RNA polymerase (Nsp12) are also attractive drug targets for this disease. The main aim of this review is gathering information about medicinal plants with antiviral properties from plant database.

MicroRNA Heterogeneity, Innate-Immune Defense and the Efficacy of SARS-CoV-2 Infection-A Commentary.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), a member of the genus Betacoronavirus in the family Coronaviridae, possesses an unusually large single-stranded viral RNA (ssvRNA) genome of about ~29,811 nucleotides (nt) that causes severe and acute respiratory distress and a highly lethal viral pneumonia known as COVID-19. COVID-19 also presents with multiple ancillary systemic diseases and often involves cardiovascular, inflammatory, and/or neurological complications. Pathological viral genomes consisting of ssvRNA, like cellular messenger RNA (mRNA), are susceptible to attack, destruction, neutralization, and/or modulation by naturally occurring small non-coding RNAs (sncRNAs) within the host cell, some of which are known as microRNAs (miRNAs). This paper proposes that the actions of the 2650 known human miRNAs and other sncRNAs form the basis for an under-recognized and unappreciated innate-immune regulator of ssvRNA viral genome activities and have implications for the efficiency of SARS-CoV-2 invasion, infection, and replication. Recent research indicates that both miRNA and mRNA abundance, speciation, and complexity varies widely amongst human individuals, and this may: (i) In part explain the variability in the innate-immune immunological and pathophysiological response of different human individuals to the initiation and progression of SARS-CoV-2 infection in multiple tissue types; and (ii) further support our understanding of human biochemical and genetic individuality and the variable resistance of individuals to ssvRNA-mediated viral infection and disease. This commentary will briefly address current findings and concepts in this fascinating research area of non-coding RNA and innate-immunity with special reference to natural host miRNAs, SARS-CoV-2, and the current COVID-19 pandemic.

Management of cases of COVID-19 infection with acute respiratory failure: a narrative review

Corona viruses are enveloped, positive-sense, single-stranded large RNA viruses that affect humans and many animals. About 5% of COVID-19 patients need ICU admission due to ARDS, with a case fatality rate varying from 30% to 60%. Some patients need help other than supplementary oxygen, such as non-invasive ventilation or intubation. Before deciding the appropriate respiratory support for acute respiratory failure patients, concerns regarding the dangers of various treatments should be considered. During the treatment of COVID-19 patients, all respiratory therapies face a risk of aerosol-generating procedures. When treating COVID-19 patients, the priority and consideration should be personal safety devices and environmental control/engineering.

Rescue of Infectious Sindbis Virus by Yeast Spheroplast-Mammalian Cell Fusion.

Sindbis virus (SINV), a positive-sense single stranded RNA virus that causes mild symptoms in humans, is transmitted by mosquito bites. SINV reverse genetics have many implications, not only in understanding alphavirus transmission, replication cycle, and virus-host interactions, but also in biotechnology and biomedical applications. The rescue of SINV infectious particles is usually achieved by transfecting susceptible cells (BHK-21) with SINV-infectious mRNA genomes generated from cDNA constructed via in vitro translation (IVT). That procedure is time consuming, costly, and relies heavily on reagent quality. Here, we constructed a novel infectious SINV cDNA construct that expresses its genomic RNA in yeast cells controlled by galactose induction. Using spheroplasts made from this yeast, we established a robust polyethylene glycol-mediated yeast: BHK-21 fusion protocol to rescue infectious SINV particles. Our approach is timesaving and utilizes common lab reagents for SINV rescue. It could be a useful tool for the rescue of large single strand RNA viruses, such as SARS-CoV-2.

Development of Rice Stripe Tenuivirus Minireplicon Reverse Genetics Systems Suitable for Analyses of Viral Replication and Intercellular Movement.

Rice stripe virus (RSV), a tenuivirus with four negative-sense/ambisense genome segments, is one of the most devastating viral pathogens affecting rice production in many Asian countries. Despite extensive research, our understanding of RSV infection cycles and pathogenesis has been severely impaired by the lack of reverse genetics tools. In this study, we have engineered RSV minireplicon (MR)/minigenome cassettes with reporter genes substituted for the viral open reading frames in the negative-sense RNA1 or the ambisense RNA2-4 segments. After delivery to Nicotiana benthamiana leaves via agroinfiltration, MR reporter gene expression was detected only when the codon-optimized large viral RNA polymerase protein (L) was coexpressed with the nucleocapsid (N) protein. MR activity was also critically dependent on the coexpressed viral suppressors of RNA silencing, but ectopic expression of the RSV-encoded NS3 silencing suppressor drastically decreased reporter gene expression. We also developed intercellular movement-competent MR systems with the movement protein expressed either in cis from an RNA4-based MR or in trans from a binary plasmid. Finally, we generated multicomponent replicon systems by expressing the N and L proteins directly from complementary-sense RNA1 and RNA3 derivatives, which enhanced reporter gene expression, permitted autonomous replication and intercellular movement, and reduced the number of plasmids required for delivery. In summary, this work enables reverse genetics analyses of RSV replication, transcription, and cell-to-cell movement and provides a platform for engineering more complex recombinant systems.

Inhibition of anti-viral stress granule formation by coronavirus endoribonuclease nsp15 ensures efficient virus replication.

Cytoplasmic stress granules (SGs) are generally triggered by stress-induced translation arrest for storing mRNAs. Recently, it has been shown that SGs exert anti-viral functions due to their involvement in protein synthesis shut off and recruitment of innate immune signaling intermediates. The largest RNA viruses, coronaviruses, impose great threat to public safety and animal health; however, the significance of SGs in coronavirus infection is largely unknown. Infectious Bronchitis Virus (IBV) is the first identified coronavirus in 1930s and has been prevalent in poultry farm for many years. In this study, we provided evidence that IBV overcomes the host antiviral response by inhibiting SGs formation via the virus-encoded endoribonuclease nsp15. By immunofluorescence analysis, we observed that IBV infection not only did not trigger SGs formation in approximately 80% of the infected cells, but also impaired the formation of SGs triggered by heat shock, sodium arsenite, or NaCl stimuli. We further demonstrated that the intrinsic endoribonuclease activity of nsp15 was responsible for the interference of SGs formation. In fact, nsp15-defective recombinant IBV (rIBV-nsp15-H238A) greatly induced the formation of SGs, along with accumulation of dsRNA and activation of PKR, whereas wild type IBV failed to do so. Consequently, infection with rIBV-nsp15-H238A strongly triggered transcription of IFN-β which in turn greatly affected rIBV-nsp15-H238A replication. Further analysis showed that SGs function as an antiviral hub, as demonstrated by the attenuated IRF3-IFN response and increased production of IBV in SG-defective cells. Additional evidence includes the aggregation of pattern recognition receptors (PRRs) and signaling intermediates to the IBV-induced SGs. Collectively, our data demonstrate that the endoribonuclease nsp15 of IBV interferes with the formation of antiviral hub SGs by regulating the accumulation of viral dsRNA and by antagonizing the activation of PKR, eventually ensuring productive virus replication. We further demonstrated that nsp15s from PEDV, TGEV, SARS-CoV, and SARS-CoV-2 harbor the conserved function to interfere with the formation of chemically-induced SGs. Thus, we speculate that coronaviruses employ similar nsp15-mediated mechanisms to antagonize the host anti-viral SGs formation to ensure efficient virus replication.

Clinical Profile of Covid Patient

Coronaviruses are included in the subfamily Coronavirinae of the family Coronaviridae. Orthocoronavirinae or Coronavirinae are the scientific name of corona virus. The ongoing blazehappening due to the coronavirus SARS coV previously called 2019-nCOV ,started in city named Hubei province of the people’s republic of china which subsequently unrolled to various other countries. The world health organisation emergency committee announced a global health emergency in January 2020 on the grounds of rapid increase in china as well as all the international locations .initially the infection caused high morbidity and mortality in china but the incidence in other nations were low. Coronavirus is characterised by positive single stranded large RNA viruses ,enveloped and can infect humans and also a wide range of animals. According to the reports SARS-coV-2 was transferred from animal to human on sea food in market of Wuhan, China .there is no enough information about the possibility of a intermediate host.&#x0D; Pneumonia was the first clinical sign that ledto the recognition of SARS CoV 2 related disease COVID 19. Though several other symptom related to covid 19 has being defined, pneumonia is the most severe symptom. All the observations suggest that the range of incubation period is 0-24 days but the mean incubation period is 7days. symptomatic patients the clinical presentation is within 7days with complains of fever,cough,nasal congestion fatigue and other signs of upper respiratory infections which can further turn into symptoms of pneumonia in almost 75%of patients.Most corresponding signs of viral pneumonia include decrement in Oxygen saturation,chest x ray ,blood gas changes, and further imaging modality shows ground glass appearance,patchy consolidations alveoli filled with exudates and interlobular involvement pointing towards deterioration. other common blood picture is lymphopenia and increase in c reactive proteins and proinflammatory cytokines.

Towards elucidating the structure, function, and druggability of coronavirus cis-acting RNA motifs

Coronaviruses are the causative agents of mild to severe respiratory and intestinal infections in humans. They are the largest RNA viruses, which genomes and encoded RNAs are known to fold into the highly-order structures that play essential roles in the viral replication and infectivity cycle. The recent outbreaks of new pathogenic coronaviruses steered researchers’ attention into the possibility of targeting their RNAs directly with novel RNA-specific drugs and therapeutic strategies. In this manuscript, we highlight the recent biochemical and biophysical methodological advancements that yielded more in-depth insight into the structural and functional composition of coronaviruses cis-acting RNA motifs. We discuss the complexity of these RNA regulatory elements, their intermolecular interactions, post-transcriptional regulation, and their potential as druggable targets. We also indicate the location and function of unstructured and highly-conserved regions in coronaviruses RNA genomes representing viable aims for antisense oligonucleotide or CRISPR-based antiviral strategies.

Ubiquity of the SARS-CoV-2 receptor ACE2 and upregulation in limbic regions of Alzheimer's disease brain.

The major route of entry for the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) into human host cells is by means of the angiotensin-converting enzyme-2 (ACE2) transmembrane receptor. This zinc-containing carboxypeptidase and membrane-integral surface receptor is ubiquitous and widely expressed in multiple cell types. Hence SARS-CoV-2, an unusually large RNA virus that causes coronavirus disease 2019 (COVID-19) has the remarkable capacity to invade many different types of human host cells simultaneously. Although COVID-19 is generally considered to be primarily an acute respiratory disease SARS-CoV-2 also targets specific anatomical regions of the central nervous system (CNS). In the normal CNS the highest ACE2 levels of expression are found within the medullary respiratory centers of the brainstem and this, in part, may explain the susceptibility of numerous COVID-19 patients to severe respiratory distress. About ~35% of all COVID-19 patients experience neurological and neuropsychiatric symptoms, and apre-existing diagnosis of Alzheimer's disease (AD) predicts the highest risk of COVID-19 yet identified, with the highest mortality among elderly AD patients. In the current study of multiple anatomical regions of AD brains compared to age-, post-mortem interval- and gender-matched controls (n = 10 regions, n = 32 brains), ACE2 expression was found to be significantly up-regulated in AD in the occipital lobe, temporal lobe neocortex and hippocampal CA1. The temporal lobe and hippocampus of the brain are also targeted by the inflammatory neuropathology that accompanies AD, suggesting asignificant mechanistic overlap between COVID-19 and AD, strongly centered on invasion by the neurotropic SARS-CoV-2 virus via the increased presence of ACE2 receptors in limbic regions of the AD-affected brain.