PUBLICATION
Kmo restricts Salmonella in a whole organism infection model by promoting macrophage lysosomal acidification through kainate receptor antagonism
- Authors
- Goering, E.R., Clatworthy, A.E., Parada-Kusz, M., Bagnall, J., Hung, D.T.
- ID
- ZDB-PUB-251024-3
- Date
- 2025
- Source
- PLoS pathogens 21: e1013273e1013273 (Journal)
- Registered Authors
- Clatworthy, Anne, Goering, Emily, Hung, Deborah, Parada-Kusz, Margarita
- Keywords
- none
- MeSH Terms
-
- Animals
- Hydrogen-Ion Concentration
- Kainic Acid Receptors*/antagonists & inhibitors
- Kainic Acid Receptors*/metabolism
- Kynurenine/analogs & derivatives
- Kynurenine/metabolism
- Lysosomes*/metabolism
- Macrophages*/immunology
- Macrophages*/metabolism
- Macrophages*/microbiology
- Salmonella Infections*/immunology
- Salmonella Infections*/metabolism
- Salmonella typhimurium*/immunology
- Zebrafish
- PubMed
- 41129589 Full text @ PLoS Pathog.
Citation
Goering, E.R., Clatworthy, A.E., Parada-Kusz, M., Bagnall, J., Hung, D.T. (2025) Kmo restricts Salmonella in a whole organism infection model by promoting macrophage lysosomal acidification through kainate receptor antagonism. PLoS pathogens. 21:e1013273e1013273.
Abstract
The kynurenine pathway of tryptophan degradation has been implicated in various diseases including cancer, neurodegenerative disorders, and infectious diseases. A key branchpoint in this pathway is production of the metabolite 3-hydroxy-kynurenine (3-HK) by the enzyme kynurenine 3-monooxygenase (Kmo). We have previously reported that administration of exogenous 3-HK promotes survival of zebrafish larvae to Salmonella Typhimurium infection by restricting bacterial expansion via a systemic mechanism that targets kainate sensitive glutamate receptor (KAR) ion channels and that the endogenous production of 3-HK by Kmo is required for defense against systemic Salmonella infection. Here we show that endogenous 3-HK promotes lysosomal acidification to contribute to macrophage microbicidal activity, with its absence leading to increased host susceptibility to infection. Further, 3-HK promotes lysosomal acidification in a KAR-dependent manner. We thus reveal a novel link between KARs and macrophage lysosomal acidification, and a novel mechanism by which 3-HK promotes control of bacterial infection.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping