Hif-1alpha induced expression of Il-1beta protects against mycobacterial infection in zebrafish

Drug resistant mycobacteria are a rising problem worldwide. There is an urgent need to understand the immune response to TB to identify host targets that, if targeted therapeutically, could be used to tackle these currently untreatable infections. Here, we use an Il-1{beta} fluorescent transgenic line to show that there is an early innate immune pro-inflammatory response to well-established zebrafish models of inflammation and Mycobacterium marinum (Mm) infection. We demonstrate that host-derived hypoxia signalling, mediated by the Hif-1 transcription factor, can prime macrophages with increased levels of Il-1{beta} in the absence of infection, upregulating neutrophil antimicrobial nitric oxide production, leading to greater protection against infection. Our data link Hif-1 to proinflammatory macrophage Il-1{beta} transcription in vivo during early mycobacterial infection and importantly highlight a host protective mechanism, via antimicrobial nitric oxide, that decreases disease outcomes and that could be targeted therapeutically to stimulate the innate immune response to better deal with infections.