Candida albicanssuppression of neutrophil reactive nitrogen species is rescued by host Hif-1αin vivo

Abstract

AbstractCandidaspp. 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 albicansis a human commensal fungus that can cause life-threatening invasive infection in immunocompromised individuals.C. albicansis able to manipulate host macrophages and neutrophils to escape phagosomal killing and has previously been shown to suppress reactive nitrogen species (RNS) productionin vitro. However, the effects ofC. albicanson RNSin vivoand the molecular and cellular mechanisms involved remain unclear. Using a zebrafish model, we aimed to characterise RNS suppression byC. albicans in vivo. We demonstrate thatC. albicanssuppressed neutrophil RNS both proximally and distally to the infection site in a partially active process, with heat-killedC. albicansnot reducing RNS to the same extent as live fungi. Using acar1Δ mutant, we show that fungal arginase is partially responsible for the reduction in neutrophil RNS. Stabilisation of Hif-1α, a transcription factor with a key role in immune regulation, rescued neutrophil RNS production duringC. albicansinfection, leading to improved infection outcomes. The protective effect of Hif-1α stabilisation was neutrophil- and nitric oxide synthase-dependent. Together, these data demonstrate that Hif-1α stabilisation can restore the neutrophil RNS response inC. albicansinfection, leading to improved infection outcomes, highlighting the potential of targeting Hif-1α and RNS in host directed therapies against fungal infections.