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Interactions De La Protéine Nsp1 Du Virus Chikungunya Avec Les Membranes De L’Hôte Et Conséquences Fonctionnelles William Bakhache
Interactions de la protéine nsP1 du virus Chikungunya avec les membranes de l’hôte et conséquences fonctionnelles William Bakhache To cite this version: William Bakhache. Interactions de la protéine nsP1 du virus Chikungunya avec les membranes de l’hôte et conséquences fonctionnelles. Médecine humaine et pathologie. Université Montpellier, 2020. Français. NNT : 2020MONTT008. tel-03132645 HAL Id: tel-03132645 https://tel.archives-ouvertes.fr/tel-03132645 Submitted on 5 Feb 2021 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. THÈSE POUR OBTENIR LE GRADE DE DOCTEUR DE L’UNIVERSITÉ DE M ONTPELLIER En Biologie Santé École Doctorale Sciences Chimiques et Biologiques pour la Santé UMR 9004 - Institut de Recherche en Infectiologie de Montpellier Interactions de la protéine nsP1 du virus Chikungunya avec les membranes de l’hôte et conséquences fonctionnelles Présentée par William Bakhache Le 27 Mars 2020 Sous la direction de Laurence Briant Devant le jury composé de Jean-Luc Battini, Directeur de Recherche, IRIM, Montpellier Président de jury Ali Amara, Directeur de recherche, U944 INSERM, Paris Rapporteur Juan Reguera, Chargé de recherche, AFMB, Marseille Rapporteur Raphaël Gaudin, Chargé de recherche, IRIM, Montpellier Examinateur Yves Rouillé, Directeur de Recherche, CIIL, Lille Examinateur Bruno Coutard, Professeur des universités, UVE, Marseille Co-encadrant de thèse Laurence Briant, Directeur de recherche, IRIM, Montpellier Directeur de thèse 1 Acknowledgments I want to start by thanking the members of my thesis jury. -
Viral Strategies to Arrest Host Mrna Nuclear Export
Viruses 2013, 5, 1824-1849; doi:10.3390/v5071824 OPEN ACCESS viruses ISSN 1999-4915 www.mdpi.com/journal/viruses Review Nuclear Imprisonment: Viral Strategies to Arrest Host mRNA Nuclear Export Sharon K. Kuss *, Miguel A. Mata, Liang Zhang and Beatriz M. A. Fontoura Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; E-Mails: [email protected] (M.A.M.); [email protected] (L.Z.); [email protected] (B.M.A.F) * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +1-214-633-2001; Fax: +1-214-648-5814. Received: 10 June 2013; in revised form: 27 June 2013 / Accepted: 11 July 2013 / Published: 18 July 2013 Abstract: Viruses possess many strategies to impair host cellular responses to infection. Nuclear export of host messenger RNAs (mRNA) that encode antiviral factors is critical for antiviral protein production and control of viral infections. Several viruses have evolved sophisticated strategies to inhibit nuclear export of host mRNAs, including targeting mRNA export factors and nucleoporins to compromise their roles in nucleo-cytoplasmic trafficking of cellular mRNA. Here, we present a review of research focused on suppression of host mRNA nuclear export by viruses, including influenza A virus and vesicular stomatitis virus, and the impact of this viral suppression on host antiviral responses. Keywords: virus; influenza virus; vesicular stomatitis virus; VSV; NS1; matrix protein; nuclear export; nucleo-cytoplasmic trafficking; mRNA export; NXF1; TAP; CRM1; Rae1 1. Introduction Nucleo-cytoplasmic trafficking of proteins and RNA is critical for proper cellular functions and survival. -
A SARS-Cov-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-Repurposing
A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-Repurposing Supplementary Information Supplementary Discussion All SARS-CoV-2 protein and gene functions described in the subnetwork appendices, including the text below and the text found in the individual bait subnetworks, are based on the functions of homologous genes from other coronavirus species. These are mainly from SARS-CoV and MERS-CoV, but when available and applicable other related viruses were used to provide insight into function. The SARS-CoV-2 proteins and genes listed here were designed and researched based on the gene alignments provided by Chan et. al. 1 2020 . Though we are reasonably sure the genes here are well annotated, we want to note that not every protein has been verified to be expressed or functional during SARS-CoV-2 infections, either in vitro or in vivo. In an effort to be as comprehensive and transparent as possible, we are reporting the sub-networks of these functionally unverified proteins along with the other SARS-CoV-2 proteins. In such cases, we have made notes within the text below, and on the corresponding subnetwork figures, and would advise that more caution be taken when examining these proteins and their molecular interactions. Due to practical limits in our sample preparation and data collection process, we were unable to generate data for proteins corresponding to Nsp3, Orf7b, and Nsp16. Therefore these three genes have been left out of the following literature review of the SARS-CoV-2 proteins and the protein-protein interactions (PPIs) identified in this study. -
Thiopurines Activate an Antiviral Unfolded Protein Response That
bioRxiv preprint doi: https://doi.org/10.1101/2020.09.30.319863; this version posted October 1, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 Thiopurines activate an antiviral unfolded protein response that blocks viral glycoprotein 2 accumulation in cell culture infection model 3 Patrick Slaine1, Mariel Kleer 2, Brett Duguay 1, Eric S. Pringle 1, Eileigh Kadijk 1, Shan Ying 1, 4 Aruna D. Balgi 3, Michel Roberge 3, Craig McCormick 1, #, Denys A. Khaperskyy 1, # 5 6 1Department of Microbiology & Immunology, Dalhousie University, 5850 College Street, Halifax 7 NS, Canada B3H 4R2 8 2Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, 3330 9 Hospital Drive NW, Calgary AB, Canada T2N 4N1 10 3Department of Biochemistry and Molecular Biology, 2350 Health Sciences Mall, University of 11 British Columbia, Vancouver BC, Canada V6T 1Z3 12 13 14 #Co-corresponding authors: C.M., [email protected], D.A.K., [email protected] 15 16 17 Running Title: Drug-induced antiviral unfolded protein response 18 Keywords: virus, influenza, coronavirus, SARS-CoV-2, thiopurine, 6-thioguanine, 6- 19 thioguanosine, unfolded protein response, hemagglutinin, neuraminidase, glycosylation, host- 20 targeted antiviral 21 22 23 ABSTRACT 24 Enveloped viruses, including influenza A viruses (IAVs) and coronaviruses (CoVs), utilize the 25 host cell secretory pathway to synthesize viral glycoproteins and direct them to sites of assembly. 26 Using an image-based high-content screen, we identified two thiopurines, 6-thioguanine (6-TG) 27 and 6-thioguanosine (6-TGo), that selectively disrupted the processing and accumulation of IAV 28 glycoproteins hemagglutinin (HA) and neuraminidase (NA). -
Functional Studies of the Coronavirus Nonstructural Proteins Yanglin QIU and Kai XU*
REVIEW ARTICLE Functional studies of the coronavirus nonstructural proteins Yanglin QIU and Kai XU* Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life Sciences, Nanjing Normal University, Nanjing 210023, P. R. China. *Correspondence: [email protected] https://doi.org/10.37175/stemedicine.v1i2.39 ABSTRACT Coronaviruses, including SARS-CoV, SARS-CoV-2, and MERS-CoV, have caused contagious and fatal respiratory diseases in humans worldwide. Notably, the coronavirus disease 19 (COVID-19) caused by SARS-CoV-2 spread rapidly in early 2020 and became a global pandemic. The nonstructural proteins of coronaviruses are critical components of the viral replication machinery. They function in viral RNA transcription and replication, as well as counteracting the host innate immunity. Studies of these proteins not only revealed their essential role during viral infection but also help the design of novel drugs targeting the viral replication and immune evasion machinery. In this review, we summarize the functional studies of each nonstructural proteins and compare the similarities and differences between nonstructural proteins from different coronaviruses. Keywords: Coronavirus · SARS-CoV-2 · COVID-19 · Nonstructural proteins · Drug discovery Introduction genes (18). The first two major ORFs (ORF1a, ORF1ab) The coronavirus (CoV) outbreaks among human are the replicase genes, and the other four encode viral populations have caused three major epidemics structural proteins that comprise the essential protein worldwide, since the beginning of the 21st century. These components of the coronavirus virions, including the spike are the epidemics of the severe acute respiratory syndrome surface glycoprotein (S), envelope protein (E), matrix (SARS) in 2003 (1, 2), the Middle East respiratory protein (M), and nucleocapsid protein (N) (14, 19, 20). -
Virus-Host Interaction: the Multifaceted Roles of Ifitms And
Virus-Host Interaction: The Multifaceted Roles of IFITMs and LY6E in HIV Infection DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Jingyou Yu Graduate Program in Comparative and Veterinary Medicine The Ohio State University 2018 Dissertation Committee: Shan-Lu Liu, MD, PhD, Advisor Patrick L. Green, PhD Jianrong Li, DVM., PhD Jesse J. Kwiek, PhD Copyrighted by Jingyou Yu 2018 Abstract With over 1.8 million newly infected people each year, the worldwide HIV-1 epidemic remains an imperative challenge for public health. Recent work has demonstrated that type I interferons (IFNs) efficiently suppress HIV infection through induction of hundreds of interferon stimulated genes (ISGs). These ISGs target distinct infection stages of invading pathogens and shape innate immunity. Among these, interferon induced transmembrane proteins (IFITMs) and lymphocyte antigen 6 complex, locus E (LY6E) have been shown to differentially modulate viral infections. However, their effects on HIV are not fully understood. In my thesis work, I provided evidence in Chapter 2 showing that IFITM proteins, particularly IFITM2 and IFITM3, specifically antagonize the HIV-1 envelope glycoprotein (Env), thereby inhibiting viral infection. IFITM proteins interacted with HIV-1 Env in viral producer cells, leading to impaired Env processing and virion incorporation. Notably, the level of IFITM incorporation into HIV-1 virions did not strictly correlate with the extent of inhibition. Prolonged passage of HIV-1 in IFITM-expressing T lymphocytes led to emergence of Env mutants that overcome IFITM restriction. The ability of IFITMs to inhibit cell-to-cell infection can be extended to HIV-1 primary isolates, HIV-2 and SIVs; however, the extent of inhibition appeared to be virus- strain dependent. -
Rotavirus Strategies to Take Over the Host Cell Response
Rotavirus strategies to take over the host cell response Instituto de Biotecnología Universidad Nacional Autónoma de México Battle between viruses and host cells Viral counter-measures Virus Host Host cell defenses During rotavirus infection the cellular protein synthesis is shutoff Virus - + During infection NSP3 displaces PABP from eIF4G and prevents cellular protein synthesis mRNA AAAA NSP3PABP 4A eIF4G Cap 4E eIF4F During RV infection, PABP relocalizes to the nucleus, and this depends on NSP3 a-PABP a-eIF4GI merge - virus control a-NSP2 + virus siIrr siNSP3 Montero H et al, 2006, J Virol. 80:9031-9038 polyA+ mRNAs are also relocalized in the nucleus of the cell during infection probe :Oligo dT No probe No Virus siIrr aNSP3 Merge + Virus siIrr + Virus siNSP3 Rubio RM et al, 2013. J Virol. During RV infection cellular mRNAs accumulate in the nucleus GRP78 GRP94 Cytop 5 Nuc 4 1.0 3 2 0.5 1 Relative amount Relative of amount Relative amount Relative of amount RNA units)(arbitrary RNA RNA units)(arbitrary RNA 0 0.0 Mock 6h 12h s/v 6h 12h Hours postinfection Hours postinfection Rotavirus prevents host translation by blocking the nucleo-cytoplasmic transport of poly(A)-containing mRNAs Rubio RM et al, 2013. J Virol eIF2a is phosphorylated during rotavirus infection hr post-infection: s/v 1 2 3 4 5 6 7 8 10 12 anti-eIF2ap Rojas M et al, 2010. J Virol. Translation factor eIF2 a GTP eIF2B GTP GDP a GDP GDP Met a a eIF2B GTP GDP Global translation inhibition Selective synthesis Translation initiation Rotavirus infection induces phosphorylation of eIF2a in a PKR-dependent manner MEFs: PERK-/- WT PKR-/- MA104 - Tg Ar Tg - Tg - Irr siPKR α-eIF2α-P eIF2a-P eIF2a PKR Rojas M et al, 2010. -
In Vitro Evolution of High-Titer, Virus-Like Vesicles Containing a Single Structural Protein
In vitro evolution of high-titer, virus-like vesicles containing a single structural protein Nina F. Rosea, Linda Buonocorea, John B. Schella, Anasuya Chattopadhyaya, Kapil Bahla, Xinran Liub, and John K. Rosea,1 aDepartment of Pathology, Yale University School of Medicine, New Haven, CT 06510; and bCenter for Cellular and Molecular Imaging, Yale University School of Medicine, New Haven, CT 06510 Edited* by Robert A. Lamb, Northwestern University, Evanston, IL, and approved October 22, 2014 (received for review August 6, 2014) Self-propagating, infectious, virus-like vesicles (VLVs) are gener- RNA. These proteins form a complex that directs replication of ated when an alphavirus RNA replicon expresses the vesicular the genomic RNA to form antigenomic RNA, which is then stomatitis virus glycoprotein (VSV G) as the only structural protein. copied to form full-length positive strand RNA and a subgenomic The mechanism that generates these VLVs lacking a capsid protein mRNA that encodes the structural proteins. The capsid protein has remained a mystery for over 20 years. We present evidence encases the genomic RNA in the cytoplasm and then buds from that VLVs arise from membrane-enveloped RNA replication facto- the cell surface in a membrane containing the SFV glycoproteins. ries (spherules) containing VSV G protein that are largely trapped Alphavirus RNA replication occurs inside light-bulb shaped, on the cell surface. After extensive passaging, VLVs evolve to membrane-bound compartments called spherules that initially grow to high titers through acquisition of multiple point muta- form on the cell surface and are then endocytosed to form cyto- tions in their nonstructural replicase proteins. -
Viral Vectors Applied for Rnai-Based Antiviral Therapy
viruses Review Viral Vectors Applied for RNAi-Based Antiviral Therapy Kenneth Lundstrom PanTherapeutics, CH1095 Lutry, Switzerland; [email protected] Received: 30 July 2020; Accepted: 21 August 2020; Published: 23 August 2020 Abstract: RNA interference (RNAi) provides the means for alternative antiviral therapy. Delivery of RNAi in the form of short interfering RNA (siRNA), short hairpin RNA (shRNA) and micro-RNA (miRNA) have demonstrated efficacy in gene silencing for therapeutic applications against viral diseases. Bioinformatics has played an important role in the design of efficient RNAi sequences targeting various pathogenic viruses. However, stability and delivery of RNAi molecules have presented serious obstacles for reaching therapeutic efficacy. For this reason, RNA modifications and formulation of nanoparticles have proven useful for non-viral delivery of RNAi molecules. On the other hand, utilization of viral vectors and particularly self-replicating RNA virus vectors can be considered as an attractive alternative. In this review, examples of antiviral therapy applying RNAi-based approaches in various animal models will be described. Due to the current coronavirus pandemic, a special emphasis will be dedicated to targeting Coronavirus Disease-19 (COVID-19). Keywords: RNA interference; shRNA; siRNA; miRNA; gene silencing; viral vectors; RNA replicons; COVID-19 1. Introduction Since idoxuridine, the first anti-herpesvirus antiviral drug, reached the market in 1963 more than one hundred antiviral drugs have been formally approved [1]. Despite that, there is a serious need for development of novel, more efficient antiviral therapies, including drugs and vaccines, which has become even more evident all around the world today due to the recent coronavirus pandemic [2]. -
In Silico Studies Reveal Potential Antiviral Activity of Phytochemicals from Medicinal Plants for the Treatment of COVID-19 Infection
In silico studies reveal potential antiviral activity of phytochemicals from medicinal plants for the treatment of COVID-19 infection Mansi Pandit Bioinformatics center, Sri Venkateswara College, University of Delhi N. Latha ( [email protected] ) Bioinformatics center, Sri Venkateswara College, University of Delhi Research Article Keywords: SARS-CoV-2, Drug Targets, Phytochemicals, Medicinal Plants, Docking, Binding energy Posted Date: April 14th, 2020 DOI: https://doi.org/10.21203/rs.3.rs-22687/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Page 1/31 Abstract The spread of COVID-19 across continents has led to a global health emergency. COVID-19 disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has affected nearly all the continents with around 1.52 million conrmed cases worldwide. Currently only a few regimes have been suggested to ght the infection and no specic antiviral agent or vaccine is available. Repurposing of the existing drugs or use of natural products are the fastest options available for the treatment. The present study is aimed at employing computational approaches to screen phytochemicals from the medicinal plants targeting the proteins of SARS-CoV2 for identication of antiviral therapeutics. The study focuses on three target proteins important in the life cycle of SARS-CoV- 2 namely Spike (S) glycoprotein, main protease (Mpro) and RNA-dependent RNA-polymerase (RdRp). Molecular docking was performed to screen phytochemicals in medicinal plants to determine their feasibility as potential inhibitors of these target viral proteins. Of the 30 plant phytochemicals screened, Silybin, an active constituent found in Silybum marianum exhibited higher binding anity with targets in SARS-CoV-2 in comparison to currently used repurposed drugs against SARS-CoV-2. -
APICAL M2 PROTEIN IS REQUIRED for EFFICIENT INFLUENZA a VIRUS REPLICATION by Nicholas Wohlgemuth a Dissertation Submitted To
APICAL M2 PROTEIN IS REQUIRED FOR EFFICIENT INFLUENZA A VIRUS REPLICATION by Nicholas Wohlgemuth A dissertation submitted to Johns Hopkins University in conformity with the requirements for the degree of Doctor of Philosophy Baltimore, Maryland October, 2017 © Nicholas Wohlgemuth 2017 All rights reserved ABSTRACT Influenza virus infections are a major public health burden around the world. This dissertation examines the influenza A virus M2 protein and how it can contribute to a better understanding of influenza virus biology and improve vaccination strategies. M2 is a member of the viroporin class of virus proteins characterized by their predicted ion channel activity. While traditionally studied only for their ion channel activities, viroporins frequently contain long cytoplasmic tails that play important roles in virus replication and disruption of cellular function. The currently licensed live, attenuated influenza vaccine (LAIV) contains a mutation in the M segment coding sequence of the backbone virus which confers a missense mutation (alanine to serine) in the M2 gene at amino acid position 86. Previously discounted for not showing a phenotype in immortalized cell lines, this mutation contributes to both the attenuation and temperature sensitivity phenotypes of LAIV in primary human nasal epithelial cells. Furthermore, viruses encoding serine at M2 position 86 induced greater IFN-λ responses at early times post infection. Reversing mutations such as this, and otherwise altering LAIV’s ability to replicate in vivo, could result in an improved LAIV development strategy. Influenza viruses infect at and egress from the apical plasma membrane of airway epithelial cells. Accordingly, the virus transmembrane proteins, HA, NA, and M2, are all targeted to the apical plasma membrane ii and contribute to egress. -
Role of the Interaction Between Large T Antigen and Rb Family Members in the Oncogenicity of JC Virus
Oncogene (2006) 25, 5294–5301 & 2006 Nature Publishing Group All rights reserved 0950-9232/06 $30.00 www.nature.com/onc REVIEW Role of the interaction between large T antigen and Rb family members in the oncogenicity of JC virus V Caracciolo1, K Reiss2, K Khalili2, G De Falco1,3 and A Giordano1,3 1Department of Biology, Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, Philadelphia, PA, USA; 2Department of Neuroscience, Center for Neurovirology, Temple University, Philadelphia, PA, USA and 3Department of Human Pathology and Oncology, University of Siena, Siena, Italy Human polyomaviruses (JC virus,BK virus and simian stimulating DNA replication (Cinatl and Doerr, virus 40) are causative agents of some human diseases 2001).Indeed, DNA viruses depend on the replication and,interestingly,are involved in processes of cell machinery of the host cell to complete viral replication transformation and oncogenesis. These viruses need the cycle.As the enzymes for DNA replication are present cell cycle machinery of the host cell to complete their in sufficient amounts only during the S phase of the replication; so they evolved mechanisms that can interfere cell cycle, the viruses have evolved mechanisms to with the growth control of infected cells and force them meet this requirement.They encode proteins that into DNA replication. The retinoblastoma family of interfere with growth control mechanisms of the infected proteins (pRb),which includes pRb/p105,p107 and cells, which allow them to drive cells from quiescence pRb2/p130,acts as one of the most important regulators to DNA replication (Nemethova et al., 2004). The of the G1/S transition of the cell cycle.