Projektbeschreibung
Entschlüsselung der zentralen Modulatoren der antiviralen Immunität
Die Auslösung einer Immunantwort gegen Viren ist ein zentraler Grundstein der menschlichen Gesundheit. Das EU-finanzierte Projekt ProDAP erforscht die Wechselwirkungen zwischen Virusproteinen und Wirtsproteinen, durch welche die Immunzellantworten reguliert werden. Mithilfe von massenspektroskopischen Verfahren und statistischer Modellierung konnten die Projektforschenden Wirtsproteine identifizieren, die auf eine Virusinfektion entweder mit einer veränderten Interaktionsfähigkeit oder einer veränderten Umsatzrate reagieren. Diese Proteine scheinen bei der antiviralen Immunität eine maßgebliche Rolle zu spielen. Ihre ausführliche Charakterisierung wird daher dazu beitragen, die komplexen Signalwege der Immunantwort zu entschlüsseln. Die daraus hervorgehenden Erkenntnisse zur Regulierung der Wirt-Pathogen-Wechselwirkung werden voraussichtlich die Entwicklung neuer antiviraler Strategien ermöglichen.
Ziel
The innate antiviral defense system is of central importance to protect from viral pathogens. Its ability to mitigate a detrimental outcome of an infectious event relies on interactions that happen between viral and host-derived proteins as well as on signalling cascades that regulate the cellular response. However, despite the importance of these interactions, the involved processes and proteins are not yet fully understood.
We established state of the art mass spectrometry techniques and statistical modelling to characterise protein-protein interactions that are affected by viruses. We identified a class of proteins we name “viral affected proteins changing their interaction” (iVAPs). In addition, we established protein turnover rates of >6900 proteins in virus infected cells and identified a group of “viral affected proteins changing turnover rates” (tVAPs). tVAPs are regulated on basis of protein stabilisation, degradation or translation. Preliminary experiments show critical importance of iVAPs and tVAPs in antiviral immunity, suggesting functional similarities to Interferon stimulated genes (ISGs). Alike ISGs, VAPs therefore represent a critical component of the immune system.
ProDAP will establish the function of iVAPs and tVAPs in the antiviral immune response. Systematic screens employing depletion and overexpression experiments, integration of these data in functional networks and mechanistic follow up studies will be performed. Already identified and new candidate proteins will be tested mechanistically for their immune-regulatory capacity and their influence on virus infections in vitro and in vivo.
ProDAP will allow insights in yet unstudied modulators of host-pathogen interplay and will influence our current understanding of immune regulation in general. It is well established that ISGs are of central importance to defend virus infections and we hypothesize that VAPs may fulfil a similarly important protective function that has yet not been elucid
Wissenschaftliches Gebiet
Schlüsselbegriffe
Programm/Programme
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Finanzierungsplan
ERC-COG - Consolidator GrantGastgebende Einrichtung
80333 Muenchen
Deutschland