Corpus overview


MeSH Disease

Human Phenotype


    displaying 1 - 10 records in total 33
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    SARS-CoV-2 in-vitro neutralization assay reveals inhibition of virus entry by iota-carrageenan

    Authors: Martina Morokutti-Kurz; Philipp Graf; Andreas Grassauer; Eva Prieschl-Grassauer

    doi:10.1101/2020.07.28.224733 Date: 2020-07-28 Source: bioRxiv

    In the absence of a vaccine and other effective prophylactic or therapeutic countermeasures the severe acute respiratory syndrome MESHD-related coronavirus 2 (SARS-CoV-2) remains a significant public health threat. Attachment and entry of coronaviruses including SARS-CoV-2 is mediated by the spike glycoprotein (SGP). Recently, a SARS-CoV-2 Spike Pseudotyped Lentivirus (SSPL) was developed that allows studying spike-mediated cell entry via luciferase reporter activity in a BSL2 environment. Here, we show that iota-carrageenan can inhibit the cell entry of SSPL in a dose dependent manner. SSPL particles were efficiently neutralized with an IC50 value of 2.6 {micro}g/ml iota-carrageenan. In vitro data on iota-carrageenan against various Rhino- and Coronaviruses showed similar IC50 values and translated readily into clinical effectiveness when a nasal spray containing iota-carrageenan demonstrated a reduction in severity and duration of symptoms of common cold MESHD caused by various respiratory viruses. Accordingly, our in vitro data on SSPL suggest that administration of iota-carrageenan may be an effective and safe prophylaxis or treatment for SARS-CoV-2 infections MESHD.

    COVID-19 Patients Form Memory CD8+ T Cells that Recognize a Small Set of Shared Immunodominant Epitopes in SARS-CoV-2

    Authors: Andrew P Ferretti; Tomasz Kula; Yifan Wang; Dalena MV Nguyen; Adam Weinheimer; Garrett S Dunlap; Qikai Xu; Nancy Nabilsi; Candace R Perullo; Alexander W Cristofaro; Holly J Whitton; Amy Virbasius; Kenneth J Olivier Jr.; Lyndsey B Baiamonte; Angela T Alistar; Eric D Whitman; Sarah A Bertino; Shrikanta Chattopadhyay; Gavin MacBeath

    doi:10.1101/2020.07.24.20161653 Date: 2020-07-27 Source: medRxiv

    Development of effective strategies to detect, treat, or prevent COVID-19 requires a robust understanding of the natural immune response to SARS-CoV-2, including the cellular response mediated by T cells. We used an unbiased, genome-wide screening technology, termed T-Scan, to identify specific epitopes in SARS-CoV-2 that are recognized by the memory CD8+ T cells of 25 COVID-19 convalescent patients, focusing on epitopes presented by the six most prevalent Human Leukocyte Antigen (HLA) types: A*02:01, A*01:01, A*03:01, A*11:01, A*24:02, and B*07:02. For each HLA type, the patients' T cells recognized 3-8 immunodominant epitopes that are broadly shared among patients. Remarkably, 94% of screened patients had T cells that recognized at least one of the three most dominant epitopes for a given HLA, and 53% of patients had T cells that recognized all three. Subsequent validation studies in 18 additional A*02:01 patients confirmed the presence of memory CD8+ T cells specific for the top six identified A*02:01 epitopes, and single-cell sequencing revealed that patients often have many different T cell clones targeting each epitope, but that the same T cell receptor Valpha regions are predominantly used to recognize these epitopes, even across patients. In total, we identified 29 shared epitopes across the six HLA types studied. T cells that target most of these immunodominant epitopes (27 of 29) do not cross-react with the endemic coronaviruses that cause the common cold MESHD, and the epitopes do not occur in regions with high mutational variation. Notably, only 3 of the 29 epitopes we identified reside in the spike protein, highlighting the need to design new classes of vaccines that recapitulate natural CD8+ T cell responses to SARS-CoV-2.

    Comparative multiplexed interactomics of SARS-CoV-2 and homologous coronavirus non-structural proteins identifies unique and shared host-cell dependencies

    Authors: Jonathan P Davies; Katherine M Almasy; Eli F McDonald; Lars Plate

    doi:10.1101/2020.07.13.201517 Date: 2020-07-15 Source: bioRxiv

    Human coronaviruses (hCoV) have become a threat to global health and society, as evident from the SARS outbreak in 2002 caused by SARS-CoV-1 and the most recent COVID-19 pandemic caused by SARS-CoV-2. Despite high sequence similarity between SARS-CoV-1 and -2, each strain has distinctive virulence. A better understanding of the basic molecular mechanisms mediating changes in virulence is needed. Here, we profile the virus-host protein-protein interactions of two hCoV non-structural proteins (nsps) that are critical for virus replication. We use tandem mass tag-multiplexed quantitative proteomics to sensitively compare and contrast the interactomes of nsp2 and nsp4 from three betacoronavirus strains: SARS-CoV-1, SARS-CoV-2, and hCoV-OC43 - an endemic strain associated with the common cold MESHD. This approach enables the identification of both unique and shared host cell protein binding partners and the ability to further compare the enrichment of common interactions across homologs from related strains. We identify common nsp2 interactors involved in endoplasmic reticulum (ER) Ca2+ signaling and mitochondria biogenesis. We also identifiy nsp4 interactors unique to each strain, such as E3 ubiquitin ligase complexes for SARS-CoV-1 and ER homeostasis factors for SARS-CoV-2. Common nsp4 interactors include N-linked glycosylation machinery, unfolded protein response (UPR) associated proteins, and anti-viral innate immune signaling factors. Both nsp2 and nsp4 interactors are strongly enriched in proteins localized at mitochondrial-associated ER membranes suggesting a new functional role for modulating host processes, such as calcium homeostasis, at these organelle contact sites. Our results shed light on the role these hCoV proteins play in the infection MESHD cycle, as well as host factors that may mediate the divergent pathogenesis of OC43 from SARS strains. Our mass spectrometry workflow enables rapid and robust comparisons of multiple bait proteins, which can be applied to additional viral proteins. Furthermore, the identified common interactions may present new targets for exploration by host-directed anti-viral therapeutics.

    Use of Machine Learning and Artificial Intelligence to predict SARS-CoV-2 infection MESHD from Full Blood SERO Counts in a population

    Authors: Abhirup Banerjeea; Surajit Ray; Bart Vorselaars; Joanne Kitson; Michail Mamalakis; Simonne Weeks; Mark Baker; Louise S. Mackenzie

    id:2007.06971v1 Date: 2020-07-14 Source: arXiv

    Since December 2019 the novel coronavirus SARS-CoV-2 has been identified as the cause of the pandemic COVID-19. Early symptoms overlap with other common conditions such as common cold MESHD and Influenza, making early screening and diagnosis are crucial goals for health practitioners. The aim of the study was to use machine learning (ML), an artificial neural network (ANN) and a simple statistical test to identify SARS-CoV-2 positive patients from full blood SERO counts without knowledge of symptoms or history of the individuals. The dataset included in the analysis and training contains anonymized full blood SERO counts results from patients seen at the Hospital Israelita Albert Einstein, at S\~ao Paulo, Brazil, and who had samples collected to perform the SARS-CoV-2 rt-PCR test during a visit to the hospital. Patient data was anonymised by the hospital, clinical data was standardized to have a mean of zero and a unit standard deviation. This data was made public with the aim to allow researchers to develop ways to enable the hospital to rapidly predict and potentially identify SARS-CoV-2 positive patients. We find that with full blood SERO counts random forest, shallow learning and a flexible ANN model predict SARS-CoV-2 patients with high accuracy between populations on regular wards (AUC = 94-95%) and those not admitted to hospital or in the community (AUC=80-86%). Here, AUC is the Area Under the receiver operating characteristics Curve and a measure for model performance SERO. Moreover, a simple linear combination of 4 blood SERO counts can be used to have an AUC of 85% for patients within the community. The normalised data of different blood SERO parameters from SARS-CoV-2 positive patients exhibit a decrease in platelets, leukocytes, eosinophils, basophils and lymphocytes, and an increase in monocytes.

    Longitudinal evaluation and decline of antibody SERO responses in SARS-CoV-2 infection MESHD

    Authors: Jeffrey Seow; Carl Graham; Blair Merrick; Sam Acors; Kathryn J.A. Steel; Oliver Hemmings; Aoife O'Bryne; Neophytos Kouphou; Suzanne Pickering; Rui Galao; Gilberto Betancor; Harry D Wilson; Adrian W Signell; Helena Winstone; Claire Kerridge; Nigel Temperton; Luke Snell; Karen Bisnauthsing; Amelia Moore; Adrian Green; Lauren Martinez; Brielle Stokes; Johanna Honey; Alba Izquierdo-Barras; Gill Arbane; Amita Patel; Lorcan OConnell; Geraldine O Hara; Eithne MacMahon; Sam Douthwaite; Gaia Nebbia; Rahul Batra; Rocio Martinez-Nunez; Jonathan D. Edgeworth; Stuart J.D. Neil; Michael H. Malim; Katie Doores

    doi:10.1101/2020.07.09.20148429 Date: 2020-07-11 Source: medRxiv

    Antibody SERO (Ab) responses to SARS-CoV-2 can be detected in most infected individuals 10-15 days following the onset of COVID-19 symptoms. However, due to the recent emergence of this virus in the human population it is not yet known how long these Ab responses will be maintained or whether they will provide protection from re- infection MESHD. Using sequential serum samples SERO collected up to 94 days post onset of symptoms TRANS (POS) from 65 RT-qPCR confirmed SARS-CoV-2-infected individuals, we show seroconversion in >95% of cases and neutralizing antibody SERO (nAb) responses when sampled beyond 8 days POS. We demonstrate that the magnitude of the nAb response is dependent upon the disease MESHD severity, but this does not affect the kinetics of the nAb response. Declining nAb titres were observed during the follow up period. Whilst some individuals with high peak ID50 (>10,000) maintained titres >1,000 at >60 days POS, some with lower peak ID50 had titres approaching baseline within the follow up period. A similar decline in nAb titres was also observed in a cohort of seropositive healthcare workers from Guy's and St Thomas' Hospitals. We suggest that this transient nAb response is a feature shared by both a SARS-CoV-2 infection MESHD that causes low disease MESHD severity and the circulating seasonal coronaviruses that are associated with common colds MESHD. This study has important implications when considering widespread serological testing SERO, Ab protection against re- infection MESHD with SARS-CoV-2 and the durability of vaccine protection.

    The Emerging Role of Neutrophil Extracellular Traps in Severe Acute Respiratory Syndrome MESHD Coronavirus 2 (COVID-19) 

    Authors: Angélica Arcanjo; Jorgete Logullo; Camilla Cristie Barreto Menezes; Thais Chrispim de Souza Cravalho Giangiarulo; Shana Priscila Coutinho Barroso; Adriane Todeschini; Leonardo Freire-de-Lima; Debora Ricardo Decoté; Celio Geraldo Freire-de-Lima; Fátima Conceição Silva; Wilson Savino; Alexandre Morrot

    doi:10.21203/ Date: 2020-07-06 Source: ResearchSquare

    The novel coronavirus SARS-CoV2 causes COVID-19, a highly pathogenic viral infection MESHD threatening millions. The majority of those infected are asymptomatic TRANS or mildly symptomatic showing typical clinical signs of common cold MESHD. However approximately 20% of the patients can progress to acute respiratory distress HP syndrome MESHD (ARDS) and eventually death MESHD in about 5% of cases. Recently, angiotensin-converting enzyme 2 (ACE2) has been shown to be a functional receptor for virus entry into host target cells. The upregulation of ACE2 in patients with comorbidities may represent a propensity for increased viral load and spreading of infection MESHD to extrapulmonary tissues. This systemic infection MESHD is associated with higher neutrophil to lymphocyte ratio in infected tissues and high levels of pro-inflammatory cytokines leading to an extensive microthrombus formation with multiorgan failure. Herein we investigated whether SARS-CoV2 can stimulate extracellular neutrophils traps (NETs) in a process called NETosis. We demonstrated for the first time that SARS-CoV2 in fact is able to activate NETosis in human neutrophils. Our findings indicated that this process is associated with increased levels of intracellular Reactive Oxygen Species (ROS) in neutrophils. The ROS-NET pathway plays a role in thrombosis MESHD formation and our study suggest the importance of this target for therapy approaches against disease MESHD.

    Endemic human coronaviruses induce distinct antibody SERO repertoires in adults TRANS and children TRANS

    Authors: Taushif Khan; Mahbuba Rahman; Fatima Al Ali; Susie S.Y. Huang; Amira Sayeed; Gheyath K. Nasrallah; Mohammad Rubayet Hasan; Nico Marr

    doi:10.1101/2020.06.21.163394 Date: 2020-06-22 Source: bioRxiv

    Four endemic human coronaviruses (HCoVs) are commonly associated with acute respiratory infection MESHD in humans but immune responses to these " common cold MESHD" viruses remain incompletely understood. Moreover, there is evidence emerging from independent studies which suggests that endemic HCoVs can induce broadly cross-reactive T cell responses and may thereby affect clinical outcomes of acute infections MESHD with the phylogenetically related epidemic viruses, namely MERS-CoV and SARS-CoV-2. Here we report a comprehensive retrospective analysis of CoV-specific antibody SERO specificities in a large number of samples from children TRANS and adults TRANS using Phage-Immunoprecipitation Sequencing (PhIP-Seq). We estimate the seroprevalence SERO for endemic HCoVs to range from ~4% to ~27% depending on species and cohort. Most importantly, we identified a large number of novel linear B cell epitopes of HCoV proteins and demonstrate that antibody SERO repertoires against endemic HCoVs are qualitatively different in children TRANS in comparison to the general adult TRANS population and healthy adult TRANS blood SERO bank donors. We show that anti-HCoV IgG specificities more frequently found among children TRANS target functionally important and structurally conserved regions of the HCoV spike and nucleocapsid proteins and some antibody SERO specificities are broadly cross-reactive with peptides of epidemic human and non-human coronavirus isolates. Our findings shed light on the humoral immune responses to natural infection MESHD with endemic HCoVs and may have important implications for understanding of the highly variable clinical outcomes of human coronavirus infections MESHD, for the development of prophylactic or therapeutic monoclonal antibodies SERO and vaccine design.

    Identification of a critical horseshoe-shaped region in the nsp5 (Mpro, 3CLpro) protease interdomain loop (IDL) of coronavirus mouse hepatitis MESHD hepatitis MESHD hepatitis HP virus (MHV)

    Authors: Benjamin C. Nick; Mansi C. Pandya; Xiaotao Lu; Megan E. Franke; Sean M. Callahan; Emily F. Hasik; Sean T. Berthrong; Mark R. Denison; Christopher C. Stobart

    doi:10.1101/2020.06.18.160671 Date: 2020-06-19 Source: bioRxiv

    Human coronaviruses are enveloped, positive-strand RNA viruses which cause respiratory diseases MESHD ranging in severity from the seasonal common cold MESHD to SARS and COVID-19. Of the 7 human coronaviruses discovered to date, 3 emergent and severe human coronavirus strains (SARS-CoV, MERS-CoV, and SARS-CoV-2) have recently jumped to humans in the last 20 years. The COVID-19 pandemic spawned by the emergence of SARS-CoV-2 in late 2019 has highlighted the importance for development of effective therapeutics to target emerging coronaviruses. Upon entry, the replicase genes of coronaviruses are translated and subsequently proteolytically processed by virus-encoded proteases. Of these proteases, nonstructural protein 5 (nsp5, Mpro, or 3CLpro), mediates the majority of these cleavages and remains a key drug target for therapeutic inhibitors. Efforts to develop nsp5 active-site inhibitors for human coronaviruses have thus far been unsuccessful, establishing the need for identification of other critical and conserved non-active-site regions of the protease. In this study, we describe the identification of an essential, conserved horseshoe-shaped region in the nsp5 interdomain loop (IDL) of mouse hepatitis MESHD hepatitis MESHD hepatitis HP virus (MHV), a common coronavirus replication model. Using site-directed mutagenesis and replication studies, we show that several residues comprising this horseshoe-shaped region either fail to tolerate mutagenesis or were associated with viral temperature- sensitivity SERO. Structural modeling and sequence analysis of these sites in other coronaviruses, including all 7 human coronaviruses, suggests that the identified structure and sequence of this horseshoe regions is highly conserved and may represent a new, non-active-site regulatory region of the nsp5 (3CLpro) protease to target with coronavirus inhibitors. ImportanceIn December 2019, a novel coronavirus (SARS-CoV-2) emerged in humans and triggered a pandemic which has to date resulted in over 8 million confirmed cases TRANS of COVID-19 across more than 180 countries and territories (June 2020). SARS-CoV-2 represents the third emergent coronavirus in the past 20 years and the future emergence of new coronaviruses in humans remains certain. Critically, there remains no vaccine nor established therapeutics to treat cases of COVID-19. The coronavirus nsp5 protease is a conserved and indispensable virus-encoded enzyme which remains a key target for therapeutic design. However, past attempts to target the active site of nsp5 with inhibitors have failed stressing the need to identify new conserved non-active-site targets for therapeutic development. This study describes the discovery of a novel conserved structural region of the nsp5 protease of coronavirus mouse hepatitis MESHD hepatitis MESHD hepatitis HP virus (MHV) which may provide a new target for coronavirus drug development.

    Evaluation of two commercial multiplex PCR tests for the diagnosis of acute respiratory infections MESHD in hospitalized children TRANS

    Authors: Le Wang; Shuo Yang; Xiaotong Yan; Teng Liu; Mengchuan Zhao; Dianping You; Guixia Li

    doi:10.21203/ Date: 2020-06-19 Source: ResearchSquare

    Background Acute respiratory tract infections MESHD respiratory tract infections HP (ARTI), including the common cold MESHD, pharyngitis MESHD pharyngitis HP, sinusitis MESHD sinusitis HP, otitis media MESHD otitis media HP, tonsillitis MESHD tonsillitis HP, bronchiolitis MESHD bronchiolitis HP and pneumonia MESHD pneumonia HP are the most common diagnoses among pediatric patients and account for the majority of antibiotic prescriptions. A clear and rapid diagnosis is the key to preventing antibiotic abuse. Recently, based on different detection principles, many multi-target molecular analyses that can simultaneously detect dozens of pathogens have been developed, thereby greatly improving sensitivity SERO and shortening turnaround time. In this work, we conducted a head-to-head comparative study between melting curve analysis (MCA) and capillary electrophoresis assay (CE) in the detection of nine respiratory pathogens in sputum samples collected from hospitalized ARTI childre TRANS.Methods Through MCA and CE analysis, nine common respiratory pathogens were tested on hospitalized children TRANS under the age TRANS of 13 who met the ARTI criteria.Results A total of 237 children TRANS with sputum specimens were tested. For all the targets combined, the positive detection rate of XYRes-MCA was significantly higher than ResP-CE (72.2% vs. 63.7%, p = .002). Some pathogens were detected more often with MCA, such as parainfluenza virus, influenza B and coronavirus, and some pathogens do the opposite, such as adenovirus and influenza A (all p < .01). Very good kappa values for most of pathogens were observed, except for Influenza B and coronavirus (both κ = .39).Conclusions Multiplex melting curve and capillary electrophoresis assays performed similarly for the detection of common respiratory pathogens in hospitalized children TRANS, except for Influenza B and coronavirus. Higher sensitivity SERO was observed in the melting curve assay. By using this sensitive and rapid test SERO, it may improv patient prognosis and antimicrobial management.

    Highly sensitive and specific multiplex antibody SERO assays to quantify immunoglobulins M, A and G against SARS-CoV-2 antigens

    Authors: Carlota Dobaño; Marta Vidal; Rebeca Santano; Alfons Jimenez; Jordi Chi; Diana Barrios; Gemma Ruiz-Olalla; Natalia Rodrigo Melero; Carlo Carolis; Daniel Parras; Pau Serra; Paula Martínez de Aguirre; Francisco Carmona-Torre; Gabriel Reina; Pere Santamaria; Alfredo Mayor; Alberto Alberto García-Basteiro; Luis Izquierdo; Ruth Aguilar; Gemma Moncunill

    doi:10.1101/2020.06.11.147363 Date: 2020-06-12 Source: bioRxiv

    Reliable serological tests SERO are required to determine the prevalence SERO of antibodies SERO against SARS-CoV-2 antigens and to characterise immunity to the disease MESHD in order to address key knowledge gaps in the context of the COVID-19 pandemic. Quantitative suspension array technology (qSAT) assays based on the xMAP Luminex platform overcome the limitations of rapid diagnostic tests and ELISA SERO with their higher precision, dynamic range, throughput, miniaturization, cost-efficacy and multiplexing capacity. We developed three qSAT assays to detect IgM, IgA and IgG to a panel of eight SARS-CoV-2 antigens including spike (S), nucleoprotein (N) and membrane (M) protein constructs. The assays were optimized to minimize processing time and maximize signal to noise ratio. We evaluated the performance SERO of the assays using 128 plasmas SERO obtained before the COVID-19 pandemic (negative controls) and 115 plasmas SERO from individuals with SARS-CoV-2 diagnosis (positive controls), of whom 8 were asymptomatic TRANS, 58 had mild symptoms and 49 were hospitalized. Pre-existing IgG antibodies SERO recognizing N, M and S2 proteins were detected in negative controls suggestive of cross-reactive to common cold MESHD coronaviruses. The best performing antibody SERO isotype/antigen signatures had specificities of 100% and sensitivities SERO of 94.94% at [≥]14 days since the onset of symptoms TRANS and 96.08% at [≥]21 days since the onset of symptoms TRANS, with AUC of 0.992 and 0.999, respectively. Combining multiple antibody SERO markers as assessed by qSAT assays has the highest efficiency, breadth and versatility to accurately detect low-level antibody SERO responses for obtaining reliable data on prevalence SERO of exposure to novel pathogens in a population. Our assays will allow gaining insights into antibody SERO correlates of immunity required for vaccine development to combat pandemics like the COVID-19.

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MeSH Disease
Human Phenotype

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