Burgess, T. B.; Hammond, F. R.; Szkuta, P. T.; Lewis, A.; Christou, S.; Ayscough, K. R.; Johnston, S. A.; Condliffe, A. M.; Elks, P. M.

Candida spp. cause 750,000 cases per annum of invasive disease worldwide, with up to a 50% mortality rate. Poor efficacy of current antifungals, lack of vaccines and rising antifungal resistance rates point towards an urgent need to develop new therapies. Candida albicans is a human commensal fungus that can cause life-threatening invasive infection in immunocompromised individuals. C. albicans is able to manipulate host macrophages and neutrophils to escape phagosomal killing and has previously been shown to suppress reactive nitrogen species (RNS) production in vitro. However, the effects of C. albicans on RNS in vivo and the molecular and cellular mechanisms involved remain unclear. Using a zebrafish model, we aimed to characterise RNS suppression by C. albicans in vivo. We demonstrate that C. albicans suppressed neutrophil RNS both proximally and distally to the infection site in a partially active process, with heat-killed C. albicans not reducing RNS to the same extent as live fungi. Using a delta-car1 mutant, we show that fungal arginase is partially responsible for the reduction in neutrophil RNS. Stabilisation of Hif-1alpha, a transcription factor with a key role in immune regulation, rescued neutrophil RNS production during C. albicans infection, leading to improved infection outcomes. The protective effect of Hif-1alpha stabilisation was neutrophil- and nitric oxide synthase-dependent. Together, these data demonstrate that Hif-1alpha stabilisation can restore the neutrophil RNS response in C. albicans infection, leading to improved infection outcomes, highlighting the potential of targeting Hif-1alpha and RNS in host directed therapies against fungal infections.