The impact of hyperammonemia in viral infection pathophysiology

Informations projet

AmmoniaVir

N° de convention de subvention: 101028971

DOI

10.3030/101028971

Projet clôturé

Date de signature de la CE 9 Mars 2021

Date de début 1 Avril 2021

Date de fin 31 Mars 2023

Financé au titre de

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Coût total

€ 174 167,04

Contribution de l’UE

€ 174 167,04

Coordonné par

CEMM - FORSCHUNGSZENTRUM FUER MOLEKULARE MEDIZIN GMBH
Austria

Periodic Reporting for period 1 - AmmoniaVir (The impact of hyperammonemia in viral infection pathophysiology)

Période du rapport: 2021-04-01 au 2023-03-31

Résumé du contexte et des objectifs généraux du projet

Signaling functions of metabolites have been gathering interest in the context of infection, cancer, and metabolic disorders. However, how metabolic communication networks shape the pathology of infection remains poorly understood. Our group has recently reported that chronic infection with lymphocytic choriomeningitis (LCMV) in mice leads to reprogramming of the hepatic urea cycle with a concomitant increase with blood ammonia levels. Despite being typically considered as a waste product with neurotoxic effect, ammonia is involved in relevant pathways for energy production, cell proliferation, and survival. In this project, I set out to identify the physiological roles of hyperammonemia during infection, including its potential contribution to sickness behavior. The main objectives were 1) to determine if hyperammonemia is a common feature of viral infections; 2) to understand what the sources and main target organs of ammonia during infection are; and 3) to uncover the (patho)physiological role of ammonia during infection. I concluded that hyperammonemia is common to different viral infections and sterile models of inflammation. I also observed an increased production of ammonia in the gut microbiota during viral infection as well as an increased uptake by the brain. These results point to an inter-organ communication mechanism whereby the activation of an antiviral immune response leads to changes in gut microbial metabolism, which can then affect the systemic metabolome with implications in the brain. This work contributes to increase our understanding of how inflammation and gut microbial metabolism influence brain function, which can have wider implications in the context of different inflammatory conditions.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

Using different experimental models of viral infection and sterile inflammation combined with metabolite tracing, imaging techniques, behavioral tests and perturbations of the gut microbiota, I uncovered a mechanism of regulation of ammonia production during infection.
I began by analyzing blood ammonia levels in several models of viral infection and inflammation and observed that hyperammonemia is a common feature of several mouse models of inflammation, indicating that it might be a by-product of the activation of an antiviral immune response. I then tried to understand which organs contribute to an increased production of ammonia during infection and identified the gut microbial metabolism to be the major source. To identify the main target organs of ammonia, I followed a metabolite tracing approach and noticed a significant uptake of ammonia in the brain, which was further increased during infection. This led me to further investigate the effects of ammonia in the brain and its contribution to behavioral changes. To this end, I performed in vitro experiments in mouse primary neurons to investigate the transcriptional response to ammonia, together with behavioral assays in mice exposed to ammonia. To further study the role of ammonia during infection, I developed strategies to modulate hyperammonemia through pharmacological interventions and through colonization of the mouse gut with bacterial strains that produce different ammonia levels.
Overall, all three proposed work packages were completed, therefore allowing for the identification of a novel gut-brain communication pathway. The results were disseminated in three scientific conferences and will be soon submitted for publication, including dissemination in open-source format.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

This project contributed to a better understanding of the pathophysiological role of small gaseous molecules in the context of infection. In particular, ammonia arises as an important player in the gut-brain axis during viral infection. The results obtained here warrant further investigation of the effects of hyperammonemia in the central nervous system and could be expanded to other gut-derived metabolites with a similar neuro-modulatory role. Overall, there is an increased recognition of the importance of metabolites produced by the gut microbiota in host physiology, but this knowledge is still very limited in the context of infection and other inflammatory conditions. Future studies in this area could open new therapeutic avenues based on specific metabolites produced by gut microbes and could therefore have a very positive impact in the treatment of inflammatory conditions.

Organism-wide effects of ammonia during infection