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The impact of hyperammonemia in viral infection pathophysiology

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.

Call for proposal

H2020-MSCA-IF-2020
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Funding Scheme

MSCA-IF-EF-SE - Society and Enterprise panel

Coordinator

CEMM - FORSCHUNGSZENTRUM FUER MOLEKULARE MEDIZIN GMBH
Address
Lazarettgasse 14 Akh Bt 25.3
1090 Wien
Austria
Activity type
Private for-profit entities (excluding Higher or Secondary Education Establishments)
EU contribution
€ 174 167,04