Menu
MapConnectionsTopicsBulgariaThe Night (K-TRIO)Marie Skłodowska-CurieFor studentsFor teachersMethodologySurprise me
H2020Individual fellowship2021–2023

AmmoniaVir · The impact of hyperammonemia in viral infection pathophysiology

Horizon 2020 — Marie Skłodowska-Curie Actions

Duration
2021-04-01 → 2023-03-31
EU contribution
€174,167
Participants
1
Scheme
MSCA-IF

Lines connect the coordinator with its partners.

Results in brief

The impact of hyperammonemia in viral infection pathophysiology

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.

Data: CORDIS, © European Union

Project objective

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. Additionally, ammonia is a small, gaseous molecule that might modulate cellular functions in distant tissues, as described for other gasotransmitters. Therefore, I hypothesize that infection-induced hyperammonemia has poorly recognized signaling functions that might influence immune responses, tissue damage, or sickness behavior. To test this hypothesis, I will combine state-of-the-art metabolic analyses, pharmacological and genetic tools. I expect to establish whether hyperammonemia is broadly associated with viral infections in mice, and/or whether it is a direct consequence of virus-induced liver damage. Additionally, I will analyze tissue-specific and organismal effects of hyperammonemia and determine whether this impacts on sickness behavior or infection outcomes. This interdisciplinary approach combining immunology, metabolism and neuroscience will allow me to characterize mechanisms of host response to viral infections, which pose outstanding challenges to current biology and medicine. Additionally, I expect to unveil inter-organ communication networks that link metabolically active tissues and the brain. These may have strong implications not only for infection but also for a wide range of metabolic disorders.

Original text from CORDIS.

Participants

  • CEMM - FORSCHUNGSZENTRUM FUER MOLEKULARE MEDIZIN GMBH · WienCoordinatorAustria

Links

Data: CORDIS, © European Union