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Host proteins required for influenza virus entry as novel antiviral targets

English title Host proteins required for influenza virus entry as novel antiviral targets
Applicant Stertz Silke
Number 176170
Funding scheme Project funding (Div. I-III)
Research institution Institut für Medizinische Virologie Universität Zürich
Institution of higher education University of Zurich - ZH
Main discipline Medical Microbiology
Start/End 01.11.2017 - 31.10.2021
Approved amount 572'000.00
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Keywords (3)

antiviral drugs; virus entry; Influenza virus

Lay Summary (German)

Lead
Obwohl wir Impfstoffe und Medikamente zur Vorbeugung und Behandlung von Influenza zur Verfügung haben, stellen Influenzaviren nach wie vor eine Gefahr für die Gesundheit des Menschen dar. Aktuell ist es daher 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, sowie neue Angriffspunkte für Medikamente, sogenannte Drug Targets, etablieren.
Lay summary
Mit diesem Antrag möchten wir zur Entwicklung neuartiger Medikamente gegen Influenza beitragen. In unseren früheren Studien haben wir zelluläre Proteine identifiziert, die beim Eintritt des Virus in die Zelle eine grosse Rolle spielen. Wir möchten nun eines der identifizierten Protein, Cathepsin W, detailiert charakterisieren und herausfinden, wie es den Eintritt der Influenzaviren in die Wirtszelle unterstützt. Langfristig sollen diese Studien klären, ob sich Cathepsin W als Ziel neuer Influenzamedikamente (Drug Target) eignet.
In einem zweiten Teil des Projekts werden wir unsere früheren Studien zu Wirtsfaktoren, die für Influenzaviren beim Zelleintritt benötigt werden, auf andere respiratorische Viren ausdehnen mit dem langfristigen Ziel, Drug Targets zu identifizieren, die die Entwicklung von antiviralen Medikamenten mit breitem Wirkspektrum ermöglichen.
Direct link to Lay Summary Last update: 10.10.2017

Responsible applicant and co-applicants

Employees

Publications

Publication
IFITM3 incorporation sensitizes influenza A virus to antibody-mediated neutralization
Lanz Caroline, Schotsaert Michael, Magnus Carsten, Karakus Umut, Hunziker Annika, Sempere Borau Milagros, Martínez-Romero Carles, Spieler Eva E., Günther Sira C., Moritz Eva, Hale Benjamin G., Trkola Alexandra, García-Sastre Adolfo, Stertz Silke (2021), IFITM3 incorporation sensitizes influenza A virus to antibody-mediated neutralization, in Journal of Experimental Medicine, 218(6), e20200303.
Entry of influenza A virus into host cells — recent progress and remaining challenges
Sempere Borau Milagros, Stertz Silke (2021), Entry of influenza A virus into host cells — recent progress and remaining challenges, in Current Opinion in Virology, 48, 23-29.
SARS-CoV-2 variants reveal features critical for replication in primary human cells
Pohl Marie O., Busnadiego Idoia, Kufner Verena, Glas Irina, Karakus Umut, Schmutz Stefan, Zaheri Maryam, Abela Irene, Trkola Alexandra, Huber Michael, Stertz Silke, Hale Benjamin G. (2021), SARS-CoV-2 variants reveal features critical for replication in primary human cells, in PLOS Biology, 19(3), e3001006-e3001006.
Interferon system deficiencies exacerbating severe pandemic virus infections
Stertz Silke, Hale Benjamin G. (2021), Interferon system deficiencies exacerbating severe pandemic virus infections, in Trends in Microbiology, S0966-842X.
Antiviral potential of 3′-sialyllactose- and 6′-sialyllactose-conjugated dendritic polymers against human and avian influenza viruses
Günther Sira Carolin, Maier Julian David, Vetter Janine, Podvalnyy Nikita, Khanzhin Nikolay, Hennet Thierry, Stertz Silke (2020), Antiviral potential of 3′-sialyllactose- and 6′-sialyllactose-conjugated dendritic polymers against human and avian influenza viruses, in Scientific Reports, 10(1), 768-768.
Application of a Biologically Contained Reporter System To Study Gain-of-Function H5N1 Influenza A Viruses with Pandemic Potential
Spieler Eva E., Moritz Eva, Stertz Silke, Hale Benjamin G. (2020), Application of a Biologically Contained Reporter System To Study Gain-of-Function H5N1 Influenza A Viruses with Pandemic Potential, in mSphere, 5(4), e00423-20.

Associated projects

Number Title Start Funding scheme
156805 The role of phosphorylation events during influenza A virus entry 01.11.2014 Project funding (Div. I-III)
164065 Entry and reassortment potential of the newly discovered bat influenza A-like viruses 01.04.2016 Project funding (Div. I-III)
204166 Novel receptors for host cell entry of influenza A viruses 01.11.2021 Project funding (Div. I-III)
135278 The influenza virus entry process - cell biological characterization and identification of novel drug targets 01.05.2011 Project funding (Div. I-III)

Abstract

Influenza viruses pose a huge burden on human health but also cause substantial economic losses due to illness-related absences from work and costs for managing influenza outbreaks in animals, such as pigs or chicken. Currently, vaccines and antiviral drugs are available, but unfortunately both come with severe limitations and novel concepts for vaccines and antivirals are needed. With our research we contribute to the development of antiviral drugs for influenza. Our approach aims to identify host cell factors required for influenza virus entry into its host cell and characterize their proviral mechanism of action. Such host factors could be exploited as drug targets if their function is essential for virus infection but not required for cell viability. Of particular interest are entry factors with a proviral catalytic function, such as proteases or kinases, as these are amenable to small molecular weight compound screening in in vitro assays.In our previous work we identified and characterized a number of entry factors for influenza virus using RNAi screening approaches but also a newly developed phospho-proteomic protocol to study host cell signaling events induced early in infection. Here, we aim to establish one of the identified entry factors, Cathepsin W, as a drug target for influenza and extend our efforts to reveal drug target candidates to other respiratory viruses.
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