Hif-1alpha stabilisation is protective against infection in a zebrafish model of comorbidity

Abstract

AbstractMulti-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-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, so it is unclear as to 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 disease-relevant settings by combining two well-characterisedin vivozebrafish models: TB infection (Mycobacterium marinuminfection) and wounding (tailfin transection). We demonstrate during systemic infection, that wounding leads to increased infection burden, but the protective effect of Hif-1α stabilisation remains. A local Mm infection near to the tailfin wound site caused neutrophil migration between sites that was reduced by Hif-1α stabilisation. Our data indicate 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 in a disease relevant setting.