Periodic Reporting for period 1 - AmmoniaVir (The impact of hyperammonemia in viral infection pathophysiology)
Période du rapport: 2021-04-01 au 2023-03-31
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.