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

Larva/immunology
Larva/metabolism
Larva/microbiology
Mycobacterium Infections, Nontuberculous/immunology*
Mycobacterium Infections, Nontuberculous/microbiology
Zebrafish Proteins/genetics
Zebrafish Proteins/immunology*
Zebrafish Proteins/metabolism
Disease Models, Animal
Animals
Neutrophils/immunology*
Neutrophils/metabolism
Mycobacterium marinum/immunology*
Mycobacterium marinum/physiology
Protein Stability
Humans
Inflammation/immunology
Inflammation/metabolism
Zebrafish/immunology*
Zebrafish/metabolism
Zebrafish/microbiology
Hypoxia-Inducible Factor 1, alpha Subunit/genetics
Hypoxia-Inducible Factor 1, alpha Subunit/immunology*
Hypoxia-Inducible Factor 1, alpha Subunit/metabolism

(all 24)

PubMed

32485057 Full text @ FEBS J.

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.

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