CE15 - Immunologie, Infectiologie et Inflammation

Triggering the production of the antiviral metabolite succinate upon influenza virus infection – Fluccinate

Submission summary

Viruses depend on host cell metabolism for their replication. As such, they have evolved sophisticated mechanisms to interfere with specific metabolic pathways in order to fulfill their need in energy and biosynthetic intermediates. On the other hand, it has been shown that signaling of innate immunity receptors induces an important metabolic reprogramming that is necessary for the initiation of an immune response and that some metabolites have immunoregulatory functions. Molecular events linking metabolism and immunity and their perturbation during a viral infection are under intense investigation and opens perspectives in the development of innovative therapeutics to control infections.
During influenza A virus (IAV) infection, a major metabolic reprogramming is observed in lungs as a result of both viral infection and activation of the immune response. Succinate has been identified recently as a predominant metabolite induced by IAV infection. It is produced in mitochondria but can be released extracellularly where it seems to play the role of a metabokine and an alarmin. Although succinate is known for activating the inflammatory response in macrophages, we recently showed that it also has a potent antiviral activity in lung epithelial cells, which is the main cell type replicating IAV, and exhibits strong protective effects in IAV-infected mice. How this antiviral and immunomodulatory metabolite is induced during IAV infection remains an open question. With this project we will address this question and identify the molecular pathways involved in the control of succinate production during IAV infection. This will allow the selection of succinate-inducing drugs whose antiviral properties will be validated ex vivo in primary human cells and lung organotypic cultures.
To do so, we will first determine which cell types are responsible for IAV-induced succinate production in the lungs by using human primary epithelial lung cells and myeloid-derived cells. To characterize the metabolic changes occurring in primary cells, in lung organotypic cultures as well as in reconstituted human airway epithelia upon IAV infection, we will combine mass spectrometry metabolomic profiling to functional assays, including Seahorse analyses and enzymatic activities. We will look for both viral and cellular molecular triggers involved in succinate induction. We will evaluate the contribution of each step of IAV replication cycle and test individually the 11 IAV proteins for their capacity to induce succinate. We will examine which innate immunity receptors and signaling pathways regulate succinate production in response to IAV infection. Data integration will be achieved using open access metabolomics databases and softwares. Identified metabolic and signaling pathways will be validated with genetic and pharmacological approaches for their role in the induction of succinate by IAV infection. Drugs targeting the validated pathways will be further evaluated ex vivo for their ability to control IAV infection in myeloid cells, reconstituted human airway epithelia and lung organotypic cultures. Overall, this project will help position succinate as a new arm of the antiviral immune response, and provide leverage to manipulate its production for therapeutic purposes.

Project coordinator

Monsieur Pierre-Olivier Vidalain (Institut national de la sante et de la recherche medicale)

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

CIRI Institut national de la sante et de la recherche medicale
CEPR Centre d'Etude des Pathologies Respiratoires
CIRI Institut national de la sante et de la recherche medicale

Help of the ANR 538,557 euros
Beginning and duration of the scientific project: September 2022 - 36 Months

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