Periodic Reporting for period 4 - ProDAP (Protein Dynamics in Antiviral Processes)
Periodo di rendicontazione: 2023-10-01 al 2024-03-31
Viruses need to enter cells and interact with cellular proteins to replicate and spread. The regulatory processes associated to virus infections are only partially understood, yet significantly contribute to successful clearance of the virus in infected patients and are causative for disease progression. Antiviral immune responses are mostly reserached by gene-centric analyses. However, it is well known that viruses interfere with de novo protein synthesis and protein stability. We hypothesized at the beginning of the project that protein interactions and protein turnover are important, yet partially neglected aspects of virus-host interactions.
The molecular functions of viruses, their effects on infected tissue and the organism directly convey into pathology and disease. Targeted intervention strategies that mitigate the influence of viruses on the organism are one option to reduce disease severety. The ERC ProDAP program focussed on interactions that are currently now known to occur in virus-infected conditions and that therefore reveal novel intervetion options. Through this process we could identify novel ways to mitigate virus growth and modulatory functions on the immune system, which we could verify in preclinical infection models.
The objective of ProDAP was the characteristaion and functional interrogation of virus-host interactions and the relevance of cellular protein turnover in infected cells. This required establising of methods and integration pipelines that describe virus-host relationships and that identify potential intervention strategies. We could establish the most comprehensive interaction database for SARS-CoV-2 and SARS-CoV, which we researched in detail during ProDAP and for which we proposed intervention strategies. The underlying algorithms could simnilarly be used for other emerging pathogens, such as the monkeypox virus and influenza A virus. Thus the obtained insights can be expanded to a wide variety of other viruses with clinical and socioeconomic importance. Prospectively ProdAP will aid intelligent design of antiviral treatment options based on in depth knowledge of a viral pathogen.
The molecular functions of viruses, their effects on infected tissue and the organism directly convey into pathology and disease. Targeted intervention strategies that mitigate the influence of viruses on the organism are one option to reduce disease severety. The ERC ProDAP program focussed on interactions that are currently now known to occur in virus-infected conditions and that therefore reveal novel intervetion options. Through this process we could identify novel ways to mitigate virus growth and modulatory functions on the immune system, which we could verify in preclinical infection models.
The objective of ProDAP was the characteristaion and functional interrogation of virus-host interactions and the relevance of cellular protein turnover in infected cells. This required establising of methods and integration pipelines that describe virus-host relationships and that identify potential intervention strategies. We could establish the most comprehensive interaction database for SARS-CoV-2 and SARS-CoV, which we researched in detail during ProDAP and for which we proposed intervention strategies. The underlying algorithms could simnilarly be used for other emerging pathogens, such as the monkeypox virus and influenza A virus. Thus the obtained insights can be expanded to a wide variety of other viruses with clinical and socioeconomic importance. Prospectively ProdAP will aid intelligent design of antiviral treatment options based on in depth knowledge of a viral pathogen.
ProDAP employed proteomic and transcriptomic approaches to identify virus interacting proteins, proteins that change their interaction profile upon virus infection and gene and proteome signatures that are regulated by these interactions. We first established essential tools to study virus-host interactions and protocols that allowed us to monitor the synthesis and degradation rates of proteins (i.e. protein turnover). We found that protein interactions and turnover are indications for involvement of the identified proteins in antiviral processes. Besides systematic analysis of the host protein interactions and protein turnover are critical denominators of virus-driven cellular processes that are associated with disease progression. Functional screens enabled us to identify proteins that have previously not been nkown to play a central importance for virus growth and/or for regulating immune responses. We further integrated knowledge from drug-protein interactions, which enabled us to idnetify molecules that influenced virus grwoth in cell culture and in pre-clinical models and which we promote further for potential therapeutic applications.
More specifically, we used the established tools to monitor the interactions and effects of viruses (e.g. SARS-CoV-2, SARS-CoV: Stulakov et al., Nature, 2021; Bergant et al., EMBO Journal, 2022; Monkeypox virus: Huang et al., Nature Communications, 2024; Influenza A virus: Huang et al., Cell Systems, 2024) and could thereby identify functionally relevant interactions and cellular processes that contribute to virus growth and antiviral processes of the individual viruses. All underlying datasets are publshed in the given manuscripts, deployed in in publically accessible repositories and accessible through websites which enable easy access for fellow scientists. Moreover, we deployed bioinformatics pipelines in public repositories, as mentioned in the manuscripts.
Given the urgency to better understand SARS-CoV-2, we focussed on this virus and could file two patents on bioactive drugs that are regulating the virus and showed favorable activities in vivo. These include one SAM-cycle inhibtior, DZNep, which inhibited SARS-CoV-2 in vitro and in vivo (Bergant et al., EMBO Journal, 2022). Interestingly, this compound not only reduced virus growth but also tamed pathology-driving inflammatory processes and improved antiviral immunity. Another compound we patented is an IKK inhibitor, which similarly reduced virus growth and is known to inhibit inflammation in vitro and in vivo.
The success of ProDAP showcases that basic knowledge on the principles of virus-host interactions can be explored to identify novel therapies that may be used for intelligent design of treatment options against virus diseases. Therefore the work within this ERC program lays the foundation for future clinical developments.
More specifically, we used the established tools to monitor the interactions and effects of viruses (e.g. SARS-CoV-2, SARS-CoV: Stulakov et al., Nature, 2021; Bergant et al., EMBO Journal, 2022; Monkeypox virus: Huang et al., Nature Communications, 2024; Influenza A virus: Huang et al., Cell Systems, 2024) and could thereby identify functionally relevant interactions and cellular processes that contribute to virus growth and antiviral processes of the individual viruses. All underlying datasets are publshed in the given manuscripts, deployed in in publically accessible repositories and accessible through websites which enable easy access for fellow scientists. Moreover, we deployed bioinformatics pipelines in public repositories, as mentioned in the manuscripts.
Given the urgency to better understand SARS-CoV-2, we focussed on this virus and could file two patents on bioactive drugs that are regulating the virus and showed favorable activities in vivo. These include one SAM-cycle inhibtior, DZNep, which inhibited SARS-CoV-2 in vitro and in vivo (Bergant et al., EMBO Journal, 2022). Interestingly, this compound not only reduced virus growth but also tamed pathology-driving inflammatory processes and improved antiviral immunity. Another compound we patented is an IKK inhibitor, which similarly reduced virus growth and is known to inhibit inflammation in vitro and in vivo.
The success of ProDAP showcases that basic knowledge on the principles of virus-host interactions can be explored to identify novel therapies that may be used for intelligent design of treatment options against virus diseases. Therefore the work within this ERC program lays the foundation for future clinical developments.
Through ProDAP we could establish the most comprehensive SARS-CoV-2 - host interaction network available to date. We publsihed several datasets and novel appraoches to characterize virus-host intearctions, which are partially published in highly respected journals and are deployed on publically available dataests.
We could show that protein interactions are important denominators of virus growth and could for the first time link virus protein-host protein interactions with downstream effects asscociated. this unprecedented detail of events enabled to identify neuralgic points in the virus-host interface and through integrating drug mode of action data, we could identify several drugs that are important for virus growth and antiviral immunity.
Another, key aspect we identified in ProDAP is the importance of protein turnover in propagation of viruses and control of their growth. We found an unexpected regulation of protein turnover of housekeeping proteins and could showcase for some that they are important for virus propagation. While we could identify proteins, which change in their turnover in virus infected cells, the underlying mechanisms on a per protein basis still remain to be elucitated. However, interference with the affected proteins modulated virus growth and antiviral processes, indicating that this yet unstudied type of regulation could potentially be explored for therapeutic intervention strategies.
We could show that protein interactions are important denominators of virus growth and could for the first time link virus protein-host protein interactions with downstream effects asscociated. this unprecedented detail of events enabled to identify neuralgic points in the virus-host interface and through integrating drug mode of action data, we could identify several drugs that are important for virus growth and antiviral immunity.
Another, key aspect we identified in ProDAP is the importance of protein turnover in propagation of viruses and control of their growth. We found an unexpected regulation of protein turnover of housekeeping proteins and could showcase for some that they are important for virus propagation. While we could identify proteins, which change in their turnover in virus infected cells, the underlying mechanisms on a per protein basis still remain to be elucitated. However, interference with the affected proteins modulated virus growth and antiviral processes, indicating that this yet unstudied type of regulation could potentially be explored for therapeutic intervention strategies.