Skip to main content
Helmholtz Munich logoHelmholtz Munich logoHelmholtz Munich logoHelmholtz Munich logoHelmholtz Munich logo
CONTACTOMICSHelmholtz Munich | ©Dr. Claudia Falter
CONTACTOMICS Grafik selbst helmholtz munich

CONTACTOMICS

The contactome, the sum of physical contacts between viral and host macromolecules, affects cellular perturbations that enable viral replication and cause disease manifestations. Because co-complex assays predominantly detect indirect protein-associations, the virus–host contactome remains largely unexplored and unknown. To address this fundamental research gap, we systematically identified protein–protein contacts between SARS-CoV-2 and the human proteome.

Research

  • EU-RIA: RiPCoN- Rapid interaction profiling of 2019-nCoV for network-based deep drug-repurpose learning (DDRL) (details s. below)
  • A map of direct SARS-CoV-2 protein interactions implicates specific human host processes. Kim, DK., Weller, B., Lin, CW. et al. A proteome-scale map of the SARS-CoV-2–human contactome. Nat Biotechnol 41, 140–149 (2023). doi.org/10.1038/s41587-022-01475-z
  • Global BioID-based SARS-CoV-2 proteins proximal interactome unveils novel ties between viral polypeptides and host factors involved in multiple COVID19-associated mechanisms. Estelle et al. bioRxiv 2020.08.28.272955
  • CLARITY - New EU project @ INET: EU-RIA: CLARITY - Causative Link between respiratory syncytial virus and chronic lung diseases: Identifying targets for therapy
  • ALS Association: Understanding and preventing virus-triggered ALS
  • Swedish Research Council: Infections in the risk and prognosis of amyotrophic lateral sclerosis (co-PI, main PI Prof. Fang Fang, Karolinska Institute)

 

 

EU RIA project number 10100363301

Project Acronym: RiPCoN

Project title: Rapid interaction profiling of 2019-nCoV for network-based deep drug-repurpose learning (DDRL)

 

01.04.2022 to 31.01.2024

PIs:

  • Prof. Pascal Falter-Braun (coordinator), Helmholtz Munich, Institute of Network Biology, Germany
  • Prof. Christine Brun, TAGC Inserm U1090, Aix-Marseille Université, France
  • Prof. Patrick Aloy, Structural Bioinformatics & Network Biology, Institute for Research in Biomedicine (IRB Barcelona), Spain

 

Summary of the RipCoN project

Fighting SARS-CoV-2 infections and treating both acute and more long-term (long COVID) cases is made difficult by the poor understanding of how the virus amplifies inside the human body. All viruses enter cells, where they modulate normal cellular functions and reprogram the cell to make thousands of new viral particles that then spread the infection inside the body and ultimately in society. The virus accomplishes this reprogramming with the help of its proteins, which bind to human proteins inside the infected cells and change their function to support the virus. Many antiviral drugs for other viruses, e.g., HIV, interfere with this reprogramming and thereby reduce and ultimately stop viral spread in the body. The challenge for SARS-CoV-2 is the lack of knowledge about which human proteins are targeted by the virus and how exactly the reprogramming of human cells is achieved.

The goal of this project is to understand which human proteins are targeted by the virus and which human molecular networks are changed and how. This important information will lead to a much-improved understanding of the biology of coronaviruses, including the more deadly SARS and MERS. More importantly, with the help of this network information, we can then use artificial intelligence and deep neural networks to identify drugs that are already on the market that revert some of the changes the virus aims to make. Therefore, it may be possible to find treatment options that do not require long and costly clinical safety testing and may become available much quicker. Moreover, we expect that the interactions we find will help understand the acute and long-term symptoms of patients suffering from COVID-19. By better understanding the molecular causes, we expect to help alleviate symptoms and aid patients.

 

Conclusions of the action:

Through our project, we have made considerable advancements in identifying and understanding the Core PAN-CoV-targeted Network, contributing to our knowledge of virus-host interactions at the molecular level. Among other findings we were able to present a systematic contactome map of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with the human host encompassing more than 200 binary virus-host and intraviral protein-protein interactions. We find that host proteins genetically associated with comorbidities of severe illness and long COVID are enriched in SARS-CoV-2 targeted network communities. Evaluating contactome-derived hypotheses, we demonstrate that viral NSP14 activates nuclear factor κB (NF-κB)-dependent transcription, even in the presence of cytokine signaling. Moreover, for several tested host proteins, genetic knock-down substantially reduces viral replication. Additionally, we show for USP25 that this effect is phenocopied by the small-molecule inhibitor AZ1. Our results connect viral proteins to human genetic architecture for COVID-19 severity and offer potential therapeutic targets. Beyond SARS-CoV-2 we have generated the first contactome map of all human coronavisuses with the human host, which coinstitutes an invaluable resource to understand coronavirus biology and thus prepare for potential future pandemics caused by viruses from this family. Intriguingly, we have identified that the extent of targeting of a molecular human network module by different coronavisues and SARS-CoV-2 strains, correlates with the lethality of the respective pathogen.

This research advances our understanding of SARS-CoV-2 mutations, viral-host interactions, and potential therapeutic targets, laying a solid foundation for future studies and antiviral strategies.

Main results are published in Kim et al, Nat Biotechnol. 2022 Oct 10. doi: 10.1038/s41587-022-01475-z. PMID: 36217029.

 

Publications of project related results:

Bertoni, M., M. Duran-Frigola, P. Badia-i-Mompel, E. Pauls, M. Orozco-Ruiz, O. Guitart-Pla, V. Alcalde, V. M. Diaz, A. Berenguer-Llergo, A. G. d. Herreros and P. Aloy (2020). Bioactivity descriptors for uncharacterized compounds. bioRxiv: 2020.2007.2021.214197.

 

Duran-Frigola, M., M. Bertoni, R. Blanco, V. Martinez, E. Pauls, V. Alcalde, G. Turon, N. Villegas, A.Fernandez-Torras, C. Pons, L. Mateo, O. Guitart-Pla, I. M. P. Badia, A. Gimeno, N. Soler, I. Brun-Heath, H. Zaragoza and P. Aloy (2020). "Bioactivity Profile Similarities to Expand the Repertoire of COVID-19 Drugs." J Chem Inf Model 60(12): 5730-5734.

 

Laurent, E. M. N., Y. Sofianatos, A. Komarova, J.-P. Gimeno, P. S. Tehrani, D.-K. Kim, H. Abdouni, M. Duhamel, P. Cassonnet, J. J. Knapp, D. Kuang, A. Chawla, D. Sheykhkarimli, A. Rayhan, R. Li, O.Pogoutse, D. E. Hill, M. A. Calderwood, P. Falter-Braun, P. Aloy, U. Stelzl, M. Vidal, A.-C. Gingras,G. A. Pavlopoulos, S. Van Der Werf, I. Fournier, F. P. Roth, M. Salzet, C. Demeret, Y. Jacob and E.Coyaud (2020). "Global BioID-based SARS-CoV-2 proteins proximal interactome unveils novel ties between viral polypeptides and host factors involved in multiple COVID19-associated mechanisms." bioRxiv: 272955.

 

Lambourne Luke et al. Binary Interactome Models of Inner- Versus Outer-Complexome Organization. bioRxiv 2021.03.16.435663; doi: doi.org/10.1101/2021.03.16.435663

 

Kim, D.-K., B. Weller, C.-W. Lin, D. Sheykhkarimli, J. J. Knapp, N. Kishore, M. Sauer, A. Rayhan, V. Young, N. Marin-de la Rosa, O. Pogoutse, K. Spirohn, A. Strobel, F. Laval, P. Schwehn, R. Li, S. Rothballer, M. Altmann, P. Cassonnet, G. Dugied, A. G. Cote, L. E. Vergara, I. Hazelwood, B. B. Liu, M. Nguyen, R. Pandiarajan, P. A. Rodriguez Coloma, L. Willems, J.-C. Twizere, C. Demeret, Y. Jacob,T. Hao, D. E. Hill, C. Falter, M. Vidal, M. A. Calderwood, F. P. Roth and P. Falter-Braun (2021). "A map of binary SARS-CoV-2 protein interactions implicates host immune regulation and ubiquitination." bioRxiv: 2021.2003.2015.433877.

 

Kim, D. K., B. Weller, C. W. Lin, D. Sheykhkarimli, J. J. Knapp, G. Dugied, A. Zanzoni, C. Pons, M. J. Tofaute, S. B. Maseko, K. Spirohn, F. Laval, L. Lambourne, N. Kishore, A. Rayhan, M. Sauer, V. Young, H. Halder, N. M. la Rosa, O. Pogoutse, A. Strobel, P. Schwehn, R. Li, S. T. Rothballer, M. Altmann, P. Cassonnet, A. G. Cote, L. E. Vergara, I. Hazelwood, B. B. Liu, M. Nguyen, R. Pandiarajan, B. Dohai, P. A. R. Coloma, J. Poirson, P. Giuliana, L. Willems, M. Taipale, Y. Jacob, T. Hao, D. E. Hill, C. Brun, J. C. Twizere, D. Krappmann, M. Heinig, C. Falter, P. Aloy, C. Demeret, M. Vidal, M.A. Calderwood, F. P. Roth and P. Falter-Braun (2022). "A proteome-scale map of the SARS-CoV-2- human contactome." Nat Biotechnol.

 

Fernández-Torras, A., A. Comajuncosa-Creus, M. Duran-Frigola and P. Aloy (2022). Connecting chemistry and biology through molecular descriptors. Current Opinion in Chemical Biology 66: 102090.

 

Fernandez-Torras, A., M. Duran-Frigola, M. Bertoni, M. Locatelli and P. Aloy (2022). Integrating and formatting biomedical data as pre-calculated knowledge graph embeddings in the Bioteque. Nat Commun 13(1): 5304.

 

Saha, D., M. Iannuccelli, C. Brun, A. Zanzoni and L. Licata (2022). "The Intricacy of the Viral-Human Protein Interaction Networks: Resources, Data, and Analyses." Front Microbiol 13: 849781.

 

Weller, B., C. W. Lin, O. Pogoutse, M. Sauer, N. Marin-de la Rosa, A. Strobel, V. Young, J. J. Knapp, A. Rayhan, C. Falter, D. K. Kim, F. P. Roth and P. Falter-Braun (2023). A resource of human coronavirus protein-coding sequences in a flexible, multipurpose Gateway Entry clone collection. G3 (Bethesda) 13(7).

 

Fernández-Torras, A., M. Locatelli, M. Bertoni and P. Aloy (2023). BQsupports: systematic assessment of the support and novelty of new biomedical associations. Bioinformatics 39(9).

 

Boes, M. and P. Falter-Braun (2023). Long- OVID-19: the persisting imprint of SARS-CoV-2 infections on the innate immune system. Signal Transduction and Targeted Therapy 8(1): 460.

 

Tofaute, Marie J., B. Weller, C. Graß, H. Halder, B. Dohai, P. Falter-Braun and D. Krappmann (2024). SARS-CoV-2 NSP14 MTase activity is critical for inducing canonical NF-κB activation. Bioscience Reports 44(1).