Hif-1alpha stabilisation is protective against infection in zebrafish comorbid models.
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.
['Schild|Yves|Y|', 'Mohamed|Abdirizak|A|', 'Wootton|Edward J|EJ|', 'Lewis|Amy|A|', 'Elks|Philip M|PM|0000-0003-1683-0749']
D000818:Animals D004195:Disease Models, Animal D006801:Humans D051795:Hypoxia-Inducible Factor 1, alpha Subunit D007249:Inflammation D007814:Larva D009165:Mycobacterium Infections, Nontuberculous D019910:Mycobacterium marinum D009504:Neutrophils D055550:Protein Stability D015027:Zebrafish D029961:Zebrafish Proteins
Zebrafish comorbid HIF Mycobacteria hypoxia