PUBLICATION
Hif-1alpha stabilisation is protective against infection in zebrafish comorbid models
- Authors
- Schild, Y., Mohamed, A., Wootton, E.J., Lewis, A., Elks, P.M.
- ID
- ZDB-PUB-200603-17
- Date
- 2020
- Source
- The FEBS journal 287(18): 3925-3943 (Journal)
- Registered Authors
- Elks, Philip
- Keywords
- Comorbid, HIF, Hypoxia, Mycobacteria, Zebrafish
- MeSH Terms
-
- Animals
- Disease Models, Animal
- Humans
- Hypoxia-Inducible Factor 1, alpha Subunit/genetics
- Hypoxia-Inducible Factor 1, alpha Subunit/immunology*
- Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
- Inflammation/immunology
- Inflammation/metabolism
- Larva/immunology
- Larva/metabolism
- Larva/microbiology
- Mycobacterium Infections, Nontuberculous/immunology*
- Mycobacterium Infections, Nontuberculous/microbiology
- Mycobacterium marinum/immunology*
- Mycobacterium marinum/physiology
- Neutrophils/immunology*
- Neutrophils/metabolism
- Protein Stability
- Zebrafish/immunology*
- Zebrafish/metabolism
- Zebrafish/microbiology
- Zebrafish Proteins/genetics
- Zebrafish Proteins/immunology*
- Zebrafish Proteins/metabolism
- PubMed
- 32485057 Full text @ FEBS J.
Citation
Schild, Y., Mohamed, A., Wootton, E.J., Lewis, A., Elks, P.M. (2020) Hif-1alpha stabilisation is protective against infection in zebrafish comorbid models. The FEBS journal. 287(18):3925-3943.
Abstract
Multi-drug resistant tuberculosis is a worldwide problem and there is an urgent need for host-derived therapeutic targets, circumventing emerging drug resistance. We have previously shown that hypoxia inducible factor-1α (Hif-1α) stabilisation helps the host to clear mycobacterial infection via neutrophil activation. However, Hif-1α stabilisation has also been implicated in chronic inflammatory diseases caused by prolonged neutrophilic inflammation. Comorbid infection and inflammation can be found together in disease settings and it remains unclear whether Hif-1α stabilisation would be beneficial in a holistic disease setting. Here, we set out to understand the effects of Hif-1α on neutrophil behaviour in a comorbid setting by combining two well-characterised in vivo zebrafish models - TB infection (Mycobacterium marinum infection) and sterile injury (tailfin transection). Using a local Mm infection near to the tailfin wound site caused neutrophil migration between the two sites that was reduced during Hif-1α stabilisation. During systemic Mm infection, wounding leads to increased infection burden, but the protective effect of Hif-1α stabilisation remains. Our data indicate that Hif-1α stabilisation alters neutrophil migration dynamics between comorbid sites, and that the protective effect of Hif-1α against Mm is maintained in the presence of inflammation, highlighting its potential as a host-derived target against TB infection.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping