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The influenza virus entry process - cell biological characterization and identification of novel drug targets

English title The influenza virus entry process - cell biological characterization and identification of novel drug targets
Applicant Stertz Silke
Number 135278
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 01.05.2011 - 31.10.2014
Approved amount 412'092.00
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Keywords (2)

influenza virus; virus entry into target cells

Lay Summary (German)

Lead
Der Eintritt des Influenzavirus in die Wirtszelle - Zellbiologische Charakterisierung und Identifizierung neuer DrugtargetsInfluenzaviren stellen eine Gefahr für die Gesundheit des Menschen dar. Aktuell sind zwar Medikamente zur Behandlung von Influenza zugelassen und erhältlich, jedoch wurde in den vergangegenen Jahren ein Anstieg der Influenzaviren, die resistent gegen die Medikamente sind, registriert. Daher ist es wichtig, neue Medikamente zur Behandlung von Influenza zu entwickeln. Dieser Antrag soll einen Beitrag zur Entwicklung neuartiger Medikamente leisten.
Lay summary
Influenzaviren besitzen ein sehr kleines Genom und kodieren nur für wenige Proteine. Die Viren sind dadurch sehr stark von ihrer Wirtszelle abhängig; so nutzen die Viren zum Beispiel zelluläre Transportwege und zelluläre Maschinerie zur Produktion neuer Viruspartikel. Mit diesem Forschungsvorhaben sollen die zellulären Proteine identifiziert und charakterisiert werden, die das Virus zum Eintritt in seine Wirtszelle nutzt. Solche zellulären Proteine, auf die das Virus beim Eintritt in die Zelle angewisen ist, stellen potentielle neue Drugtargets dar, die in Folgestudien zur Entwicklung neuer Medikamente gegen Influenzaviren genutzt werden können.

 

 

Direct link to Lay Summary Last update: 04.10.2014

Responsible applicant and co-applicants

Employees

Publications

Publication
Entry of influenza A virus: host factors and antiviral targets.
Edinger Thomas O, Pohl Marie O, Stertz Silke (2014), Entry of influenza A virus: host factors and antiviral targets., in The Journal of general virology, 95(Pt 2), 263-77.
Prolidase Is Required for Early Trafficking Events during Influenza A Virus Entry.
Pohl Marie O, Edinger Thomas O, Stertz Silke (2014), Prolidase Is Required for Early Trafficking Events during Influenza A Virus Entry., in Journal of virology, 88(19), 11271-83.
Swine IFITM proteins potently inhibit influenza A virus replication.
Lanz Caroline, Yángüez Emilio, Andenmatten Dario, Stertz Silke (2014), Swine IFITM proteins potently inhibit influenza A virus replication., in Journal of virology, 02516-14.
Glycosylations in the globular head of the hemagglutinin protein modulate the virulence and antigenic properties of the H1N1 influenza viruses.
Medina Rafael A, Stertz Silke, Manicassamy Balaji, Zimmermann Petra, Sun Xiangjie, Albrecht Randy A, Uusi-Kerttula Hanni, Zagordi Osvaldo, Belshe Robert B, Frey Sharon E, Tumpey Terrence M, García-Sastre Adolfo (2013), Glycosylations in the globular head of the hemagglutinin protein modulate the virulence and antigenic properties of the H1N1 influenza viruses., in Science translational medicine, 5(187), 187-70.
Serum- and glucocorticoid-regulated kinase 1 is required for nuclear export of the ribonucleoprotein of influenza A virus.
Alamares-Sapuay Judith G, Martinez-Gil Luis, Stertz Silke, Miller Matthew S, Shaw Megan L, Palese Peter (2013), Serum- and glucocorticoid-regulated kinase 1 is required for nuclear export of the ribonucleoprotein of influenza A virus., in Journal of virology, 87(10), 6020-6.

Associated projects

Number Title Start Funding scheme
156805 The role of phosphorylation events during influenza A virus entry 01.11.2014 Project funding
176170 Host proteins required for influenza virus entry as novel antiviral targets 01.11.2017 Project funding

Abstract

With the present proposal we aim to characterize the interaction of influenza A virus with host cell factors during the viral entry process. We will study the role of 23 host proteins that have been identified in a genome-wide RNAi screen as required host factors for influenza virus replication. Further analysis revealed that these 23 factors are specifically required for efficient influenza virus entry. We will focus our work on the identification and characterization of drugable functions, such as catalytic activities or protein-protein interactions, of these host proteins. These studies will improve our understanding of the virus-host interaction during the early stage of the viral replication cycle. Moreover, they can lead to the identification of cellular drug targets that can be exploited to develop new anti-influenza virus compounds.Aim A: Characterization of the target step of the host cell factorsIn aim A we propose to define the role of each of the 23 host cell factors during influenza virus entry. Using a set of functional assays we will dissect the entry process into four stages: binding of the virus to the host cell, endocytic uptake of the virus, endosome maturation and fusion of the viral membrane with the endosomal membrane. We will test for each entry factor which exact target step of the entry process is affected upon knockdown of expression of the respective cellular protein. Aim B: Identification of drugable functions of the host cell factorsThe goal of this part of the project is to identify drugable functions of the host cell factors that could serve as targets for future development of new anti-influenza virus drugs. We will test the requirement of the catalytic activities of the factors bearing enzymatic function for their role in virus entry. In addition, we plan to test the factors that were found to be involved in binding or uptake of the virus for direct interactions with viral proteins. Such interactions could also serve as novel targets for drug development.Aim C: Identification and characterization of COPI-interacting factors for influenza virus entryIn aim C we will focus on the COPI proteins and their role in virus entry since the results from different RNAi screens suggest that these factors are of crucial importance for the virus. We aim to identify the adaptor protein for COPI function during entry in order to identify a drugable function. Moreover, we will test their involvement in entry of other RNA viruses.
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