Project

Back to overview

Proteomic and Genetic Interrogation of the Human Interferon Response

English title Proteomic and Genetic Interrogation of the Human Interferon Response
Applicant Hale Benjamin
Number 182464
Funding scheme Project funding
Research institution Institut für Medizinische Virologie Universität Zürich
Institution of higher education University of Zurich - ZH
Main discipline Experimental Microbiology
Start/End 01.12.2018 - 31.03.2023
Approved amount 899'527.00
Show all

All Disciplines (3)

Discipline
Experimental Microbiology
Molecular Biology
Medical Microbiology

Keywords (9)

kinase; proteomics; influenza; polymorphism; phosphorylation; signaling; interferon; virus; innate immunity

Lay Summary (German)

Lead
Influenzaviren stellen eine grosse gesundheitliche Belastung für Menschen und Tiere dar. Die potentielle Übertragung von Influenzaviren aus tierischen Reservoirs auf Menschen ist eine kontinuierliche Bedrohung, welche schwerwiegende Ausbrüche und sogar Pandemien hervorrufen kann. Eine wichtige Barriere des angeborenen Immunsystems gegen zoonotische Übertragungen von Influenzaviren ist der humane Interferon-Signalweg, welcher die Stärke von saisonalen und pandemischen Ausbrüchen limitiert. Individuell angepasste Interferon-basierte Therapien könnten potente und wirtspezifische Massnahmen zur Kontrolle und Vorbeugung von Influenzaerkrankungen ermöglichen. Daher ist es kritisch, die fundamentalen Signalmechanismen zur Regulation des Interferonsystems unter normalen und pathogenen Bedingungen zu verstehen um optimale Ziele für neue Interventionsstrategien zu identifizieren.
Lay summary

In bisherigen Studien haben wir eine Gruppe von bisher nicht-charakterisierten Proteinen identifiziert, welche nach Stimulation mit Interferon modifiziert werden. Einige dieser Proteine haben sich in Folgestudien als essentiell für die Aktivierung des Interferon-Signalweges herausgestellt. In diesem Projekt möchten wir analysieren, wie diese Proteine die Interferonantwort und die Immunität auf molekularer Ebene regulieren. Dies kann unter anderem zu einem besseren Verständnis beitragen, wie natürlich vorkommende Polymorphismen in relevanten humanen Genen die Interferonantwort und die antivirale Immunabwehr beeinflussen, was wiederum mechanistischen Einblick in den Schweregrad von humanen Infektionen geben kann.

Dieses Projekt der Grundlagenforschung kann helfen, neue Erkenntnisse über die virale Abwehr des humanen angeborene Immunsystems zu gewinnen und neue Ziele für antivirale Therapien innerhalb der Interferonantwort zu identifizieren.

Direct link to Lay Summary Last update: 01.11.2018

Responsible applicant and co-applicants

Employees

Publications

Publication
Restriction factor screening identifies RABGAP1L-mediated disruption of endocytosis as a host antiviral defense
Fernbach Sonja, Spieler Eva E., Busnadiego Idoia, Karakus Umut, Lkharrazi Anouk, Stertz Silke, Hale Benjamin G. (2022), Restriction factor screening identifies RABGAP1L-mediated disruption of endocytosis as a host antiviral defense, in Cell Reports, 38(12), 110549-110549.
Antiviral immunity triggered by infection-induced host transposable elements
Hale Benjamin G (2022), Antiviral immunity triggered by infection-induced host transposable elements, in Current Opinion in Virology, 52, 211-216.
Influenza A viruses balance ER stress with host protein synthesis shutoff
Mazel-Sanchez Beryl, Iwaszkiewicz Justyna, Bonifacio Joao P. P., Silva Filo, Niu Chengyue, Strohmeier Shirin, Eletto Davide, Krammer Florian, Tan Gene, Zoete Vincent, Hale Benjamin G., Schmolke Mirco (2021), Influenza A viruses balance ER stress with host protein synthesis shutoff, in Proceedings of the National Academy of Sciences, 118(36), e202468111.
BRD9 is a druggable component of interferon‐stimulated gene expression and antiviral activity
Börold Jacob, Eletto Davide, Busnadiego Idoia, Mair Nina K, Moritz Eva, Schiefer Samira, Schmidt Nora, Petric Philipp P, Wong W Wei‐Lynn, Schwemmle Martin, Hale Benjamin G (2021), BRD9 is a druggable component of interferon‐stimulated gene expression and antiviral activity, in EMBO reports, e52823.
Combined computational and cellular screening identifies synergistic inhibition of SARS-CoV-2 by lenvatinib and remdesivir
Pohl Marie O., Busnadiego Idoia, Marrafino Francesco, Wiedmer Lars, Hunziker Annika, Fernbach Sonja, Glas Irina, Moroz-Omori Elena V., Hale Benjamin G., Caflisch Amedeo, Stertz Silke (2021), Combined computational and cellular screening identifies synergistic inhibition of SARS-CoV-2 by lenvatinib and remdesivir, in Journal of General Virology, 102(7), 1.
Manipulation of the unfolded protein response: A pharmacological strategy against coronavirus infection
Echavarría-Consuegra Liliana, Cook Georgia M., Busnadiego Idoia, Lefèvre Charlotte, Keep Sarah, Brown Katherine, Doyle Nicole, Dowgier Giulia, Franaszek Krzysztof, Moore Nathan A., Siddell Stuart G., Bickerton Erica, Hale Benjamin G., Firth Andrew E., Brierley Ian, Irigoyen Nerea (2021), Manipulation of the unfolded protein response: A pharmacological strategy against coronavirus infection, in PLOS Pathogens, 17(6), e1009644-e1009644.
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), 1.
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.
Proteomic Approaches to Dissect Host SUMOylation during Innate Antiviral Immune Responses
Lork Marie, Lieber Gauthier, Hale Benjamin G. (2021), Proteomic Approaches to Dissect Host SUMOylation during Innate Antiviral Immune Responses, in Viruses, 13(3), 528-528.
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, 1.
Antiviral Activity of Type I, II, and III Interferons Counterbalances ACE2 Inducibility and Restricts SARS-CoV-2
Busnadiego Idoia, Fernbach Sonja, Pohl Marie O., Karakus Umut, Huber Michael, Trkola Alexandra, Stertz Silke, Hale Benjamin G. (2020), Antiviral Activity of Type I, II, and III Interferons Counterbalances ACE2 Inducibility and Restricts SARS-CoV-2, in mBio, 11(5), 1.
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), 00423-20.
Profiling host ANP32A splicing landscapes to predict influenza A virus polymerase adaptation
Domingues Patricia, Eletto Davide, Magnus Carsten, Turkington Hannah L., Schmutz Stefan, Zagordi Osvaldo, Lenk Matthias, Beer Martin, Stertz Silke, Hale Benjamin G. (2019), Profiling host ANP32A splicing landscapes to predict influenza A virus polymerase adaptation, in Nature Communications, 10(1), 3396-3396.
An influenza virus-triggered SUMO switch orchestrates co-opted endogenous retroviruses to stimulate host antiviral immunity
Schmidt Nora, Domingues Patricia, Golebiowski Filip, Patzina Corinna, Tatham Michael H., Hay Ronald T., Hale Benjamin G. (2019), An influenza virus-triggered SUMO switch orchestrates co-opted endogenous retroviruses to stimulate host antiviral immunity, in Proceedings of the National Academy of Sciences, 116(35), 17399-17408.
MHC class II proteins mediate cross-species entry of bat influenza viruses
Karakus Umut, Thamamongood Thiprampai, Ciminski Kevin, Ran Wei, Günther Sira C., Pohl Marie O., Eletto Davide, Jeney Csaba, Hoffmann Donata, Reiche Sven, Schinköthe Jan, Ulrich Reiner, Wiener Julius, Hayes Michael G. B., Chang Max W., Hunziker Annika, Yángüez Emilio, Aydillo Teresa, Krammer Florian, Oderbolz Josua, Meier Matthias, Oxenius Annette, Halenius Anne, Zimmer Gert, et al. (2019), MHC class II proteins mediate cross-species entry of bat influenza viruses, in Nature, 567(7746), 109-112.

Collaboration

Group / person Country
Types of collaboration
Mirco Schmolke, University of Geneva Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Ronald T Hay, University of Dundee Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Martin Schwemmle, University of Freiburg Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Silke Stertz, University of Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel

Awards

Title Year
University of Zurich Forschungskredit Candoc 2020

Abstract

Influenza viruses cause a high human and animal disease burden with significant economic consequences. Zoonotic transmission of influenza viruses from animal reservoirs continually threatens to cause severe human outbreaks, and such spillovers can be precursors to pandemics. Human interferon (IFN) signaling constitutes a major innate barrier to zoonotic influenza virus transmission, and limits the severity of seasonal and pandemic disease. As such, tailored IFN-based therapies could provide a potent, host-directed, measure for influenza control and prevention. Understanding fundamental signaling mechanisms underlying regulation of this system during normal and pathogenic conditions is therefore critical to fully exploit this concept and to suggest optimal targets for new intervention strategies.In preliminary work, we used mass spectrometry to comprehensively survey dynamic changes to the human phosphoproteome as a cell responds to all three major IFN types (I, II & III). This revealed previously uncharacterized IFN-regulated phosphorylation events in >300 proteins, suggesting a multitude of unexplored contributions to antiviral responses. By leveraging loss- and gain- of function genetic screening of 60 core phospho-regulated proteins, we found several novel candidates that are essential for efficient IFN signaling and host defense. In this project, we will apply CRISPR/Cas9-generated knock-out cell models and reconstitution platforms to dissect molecular details by which these candidates impact IFN signaling and host immunity, and uncover the consequences, and modes of kinase regulation, that phosphorylation has on these mechanisms. In a second aim, we will develop a state-of-the-art in situ quantitative interaction proteomics technology, based on biotin ligase proximity labeling, that will be applied to selected components of the IFN system and provide a new and detailed view of the spatial and temporal regulatory protein-protein interactions that occur during IFN-type specific signaling. Finally, we will use a combination of the above techniques, and the knowledge gained, to evaluate how polymorphisms in relevant human genes impact IFN signaling and antiviral defense, thereby providing possible mechanistic insights into human infection severity.Our fundamental molecular studies should help illuminate functions of the IFN-induced signaling landscape, and thereby enhance understanding of human innate processes that confer protection against viruses. This work will build a conceptual framework within which to advance therapeutic efforts to modulate the magnitude or specificity of host IFN responses at new stages, and to identify human genetic risk determinants of disease susceptibility.
-