Project

Back to overview

The role of phosphorylation events during influenza A virus entry

English title The role of phosphorylation events during influenza A virus entry
Applicant Stertz Silke
Number 156805
Funding scheme Project funding
Research institution Institut für Medizinische Virologie Universität Zürich
Institution of higher education University of Zurich - ZH
Main discipline Medical Microbiology
Start/End 01.11.2014 - 31.10.2017
Approved amount 454'000.00
Show all

Keywords (3)

Influenza virus; Entry into target cells; Phospho-proteomics

Lay Summary (German)

Lead
Trotz erhältlichen Impfstoffen und Medikamenten stellen Influenzaviren nach wie vor eine Gefahr für die Gesundheit des Menschen dar. Daher ist es wichtig, neue Strategien zur Behandlung und Bekämpfung von Influenza zu entwickeln. Dies erfordert zunächst ein detailliertes Verständnis der Influenzaviren und ihrer Interaktion mit den Wirtszellen, in denen sich die Viren vermehren. Dieser Antrag soll einen Beitrag zum besseren Verständnis der Virus-Wirt-Interaktion liefern und somit langfristig zur Entwicklung neuer Medikamente beitragen.
Lay summary
Dieses Forschungsvorhaben hat zum Ziel, die zellulären Signaltransduktionskaskaden, die beim Eintritt von Influenzaviren in ihre Wirtszelle angeschalten werden, zu identifizieren. Es soll untersucht werden, welche zellulären Proteine dabei aktiviert werden und wie sich deren Aktivierung auf die anschliessende Vermehrung des Influenzavirus auswirkt. Einzelne Proteine, deren Aktivierung essentiell ist für die erfogreiche Virusvermehrung, könnten dann in Folgestudien mit spezifischen Hemmstoffen blockiert werden und die Auswirkung auf Virusvermehrung untersucht werden. Somit könnten potentielle neue Strategien zur Entwicklung von Medikamenten gegen Influenzaviren gefunden werden.
Direct link to Lay Summary Last update: 10.08.2016

Responsible applicant and co-applicants

Employees

Publications

Publication
Identification of Polo-like kinases as potential novel drug targets for influenza A virus.
Pohl Marie O, von Recum-Knepper Jessica, Rodriguez-Frandsen Ariel, Lanz Caroline, Yángüez Emilio, Soonthornvacharin Stephen, Wolff Thorsten, Chanda Sumit K, Stertz Silke (2017), Identification of Polo-like kinases as potential novel drug targets for influenza A virus., in Scientific reports, (1), 8629-8629.
Context-based retrieval of functional modules in protein-protein interaction networks.
Dobay Maria Pamela, Stertz Silke, Delorenzi Mauro (2017), Context-based retrieval of functional modules in protein-protein interaction networks., in Briefings in bioinformatics, 1.
Meta- and Orthogonal Integration of Influenza "OMICs" Data Defines a Role for UBR4 in Virus Budding.
Tripathi Shashank, Pohl Marie O, Zhou Yingyao, Rodriguez-Frandsen Ariel, Wang Guojun, Stein David A, Moulton Hong M, DeJesus Paul, Che Jianwei, Mulder Lubbertus C F, Yángüez Emilio, Andenmatten Dario, Pache Lars, Manicassamy Balaji, Albrecht Randy A, Gonzalez Maria G, Nguyen Quy, Brass Abraham, Elledge Stephen, White Michael, Shapira Sagi, Hacohen Nir, Karlas Alexander, Meyer Thomas F, Shales Michael, Gatorano Andre, Johnson Jeffrey R, Jang Gwen, Johnson Tasha, Verschueren Erik, Sanders Doug, Krogan Nevan, Shaw Megan, König Renate, Stertz Silke, García-Sastre Adolfo, Chanda Sumit K (2015), Meta- and Orthogonal Integration of Influenza "OMICs" Data Defines a Role for UBR4 in Virus Budding., in Cell host & microbe, (6), 723-35.
Measuring Attachment and Internalization of Influenza A Virus in A549 Cells by Flow Cytometry.
Pohl Marie O, Stertz Silke (2015), Measuring Attachment and Internalization of Influenza A Virus in A549 Cells by Flow Cytometry., in Journal of visualized experiments : JoVE, (105), 53372-53372.
Cathepsin W Is Required for Escape of Influenza A Virus from Late Endosomes.
Edinger Thomas O, Pohl Marie O, Yángüez Emilio, Stertz Silke (2015), Cathepsin W Is Required for Escape of Influenza A Virus from Late Endosomes., in mBio, (3), 00297-00297.

Collaboration

Group / person Country
Types of collaboration
Prof. Dr. Sumit Chanda United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Dr. Adolfo Garcia-Sastre United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Dr. Volker Thiel, University of Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Associated projects

Number Title Start Funding scheme
135278 The influenza virus entry process - cell biological characterization and identification of novel drug targets 01.05.2011 Project funding
176170 Host proteins required for influenza virus entry as novel antiviral targets 01.11.2017 Project funding

Abstract

Influenza viruses are of high medical concern in humans and can cause devastating economic problems for the poultry and pig livestock industries. Currently, we have some vaccines and antiviral drugs available, but both come with severe limitations. In particular, vaccines cannot protect against novel strains of influenza virus and must be continually updated. Furthermore, we experience increasing problems with drug-resistance of influenza viruses, and new antivirals with lower chances of resistance developing are urgently sought. A novel strategy currently being explored in the field is to target new antiviral drugs against host cell proteins that the virus requires for its replication. To identify such potential drug targets a detailed understanding of virus-host interactions at a molecular level is needed.Our research focuses on the entry of influenza virus into its host cell, and the virus-host interactions required during this process. This is the first key stage of infection that all influenza viruses must accomplish, and is therefore an excellent target for antiviral drugs. The entry process is a considerable engagement of the virus particle with cellular processes, including extracellular factors, membranes, and vesicle maturation and trafficking pathways, all of which must be dynamically controlled by regulatory signaling mechanisms. Here, we will unravel the phosphorylation-dependent regulatory changes that occur in the host cell early in influenza virus infection and determine their role for virus entry. Specific aims are:Aim A: To determine global changes in the host phospho-proteome that occur within minutes of virus infection using state-of-the-art proteomic methodologies in collaboration with the Functional Genomics Center Zurich. Aim B: To reveal and characterize in detail phosphorylation events that are functionally required for specific stages of virus entry using several previously established assays. This will include correlating phosphorylation events with functions of certain cellular kinases and phosphatases, both classes of enzyme that are highly ‘druggable’. Aim C: To establish a primary human tracheal/bronchial epithelial cell culture model that more closely mimics the in vivo situation for studies on influenza virus entry. We will assess changes in phosphorylation that occur upon infection and uncover their relevance for virus entry in primary respiratory epithelium using novel knock-down approaches. A better model is invaluable for possible future testing of chemical inhibitors. Our fundamental studies will help elucidate the intricate interplay between influenza virus and host cell signaling during the entry process. This knowledge should provide a framework to support future development of new anti-influenza drugs targeting host regulatory enzymes.
-