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-1 alpha (Hif-1 alpha) stabilisation helps the host to clear mycobacterial infection via neutrophil activation. However, Hif-1 alpha 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-1 alpha stabilisation would be beneficial in a holistic disease setting. Here, we set out to understand the effects of Hif-1 alpha on neutrophil behaviour in a comorbid setting by combining two well-characterisedin vivozebrafish models - TB infection (Mycobacterium marinuminfection) 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-1 alpha stabilisation. During systemic Mm infection, wounding leads to increased infection burden, but the protective effect of Hif-1 alpha stabilisation remains. Our data indicate that Hif-1 alpha stabilisation alters neutrophil migration dynamics between comorbid sites and that the protective effect of Hif-1 alpha against Mm is maintained in the presence of inflammation, highlighting its potential as a host-derived target against TB infection.