COVID-19 - Coronavirus disease 2019

Dual Profiling of the SARS-CoV2 interplay With the INnate immune response pathway – DARWIN

Submission summary

COVID-19 has emerged in December 2019 in Wuhan, China, caused by a novel RNA virus: SARS-CoV-2. As of March 22 2020, ~300,000 cases of COVID-19 and nearly 12,000 deaths (fatality rate ~4%) have been reported in the world. The high proportion of cases requiring respiratory assistance in intensive care units (~10%) catastrophically overwhelms health systems worldwide. The COVID-19 pandemic is a global health emergency and represents a never seen before challenge for the medical community but also for the scientific community which is appealed to provide prophylactics and treatment for this dreadful pathogen. Tremendous efforts are put together to counteract SARS-CoV-2 entry mechanisms and identify suitable targets for vaccine development. While generic treatments used for RNA virus infections (HIV, HCV, EBOV, ZIKV, HeV and NiV) and hydroxychloroquine are currently being investigated, no vaccine or effective treatment for SARS-CoV-2 is available or proven efficient as of today.
We propose here an original and alternative contribution to the scientific effort aiming at combatting SARS-CoV-2/host-cell innate immune escape.
Identifying the virus-host protein-protein interactions (PPIs) critical for infection will reveal mechanisms involved in pathogenesis and define promising drug targets. Through a unique combination of orthogonal state-of-the-art interactomic approaches conducted by highly qualified teams, N2H and BioID, we will timely profile the accurate interplay between SARS-CoV-2 proteins and human factors involved in anti-viral immune and consecutive inflammatory responses. As such, this project will quickly provide a wide network of potential host targets for innate immunity targeting treatment option. In a conceptually new manner, we will implement cutting-edge network modeling approaches aiming at delineating druggable disease modules. Of note, for potential transfer towards clinical applications, we will focus our testing strategies on repurposing approved drugs. Our approach could thus be exploited for developing rational and combined therapies targeting multiple elements within a disease module, at suboptimal doses, to counteract this deadly infectious process. Thus, our proposal is aligned with the topic “search for therapeutic targets and drug candidates”, especially turned here to restore the beneficial primary immune response and counter deleterious secondary inflammatory response to SARS-CoV-2 infection.
Our works are of utmost importance: (i) due to the broad distribution of COVID-19 cases over the globe and its high degree of contagiousness, the virology community expects a seasonal recurrence of such infection. It is therefore important to tackle this major issue with all means and angles available; (ii) we hope a cure for SARS-CoV-2 infection will be discovered along the course of this project. However, in case of non-satisfactory response found within the next few months, or failure to treat all the patients because of the variety of the cases, our approach will bring essential rationale to the medical and scientific communities for immediate finding of efficient cure; and (iii), assembling such workforce enabling rapid characterization of emerging infectious agent, we are deeply convinced that our works will serve as a framework easily implementable to dramatically and timely expand basic knowledge on emerging infectious mechanisms. Hence, our proposal is of major importance to bring novel insights and rationales for future therapeutic approaches. Importantly, our project will bring an unprecedented knowledge on how the SARS-CoV-2 proteins hijack the innate immune response, and because of its semi-supervised nature, will greatly expand our knowledge of SARS-CoV-2 associated mechanisms beyond innate-immunity.

Project coordination

Caroline DEMERET (Institut Pasteur)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

IP Institut Pasteur
PRISM PROTEOMIQUE, REPONSE INFLAMMATOIRE ET SPECTROMETRIE DE MASSE

Help of the ANR 169,560 euros
Beginning and duration of the scientific project: - 18 Months

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