Investigation of Candida albicans Suppression of Neutrophil Reactive Nitrogen Species in Zebrafish Larvae

Though often a harmless commensal, C. albicans causes frequent mucosal infections and can cause life-threatening, invasive infections, especially in immunocompromised individuals. Greater understanding of C. albicans pathogenesis in vivo is required. I investigated C. albicans interactions with neutrophils, using zebrafish in vivo models, aiming to unravel mechanisms of C. albicans pathogenesis and host-pathogen interactions.
Reactive nitrogen species (RNS) are a critical host antimicrobial to kill C. albicans. I showed C. albicans suppresses neutrophil RNS levels in zebrafish. Heat-killed C. albicans caused an intermediate degree of RNS suppression, implying a passive mechanism for RNS suppression. Live C. albicans suppressed neutrophil RNS proximal to the site of infection, and also distally. My data support prior observations of C. albicans suppression of mammalian macrophage RNS in vitro.
I investigated mechanisms underlying neutrophil RNS suppression by C. albicans in vivo. C. albicans hyphae and arginase (car1) were revealed to have a role in RNS suppression.
Neutrophil RNS suppression was observed across a selection of C. albicans and non-albicans Candida spp. clinical isolates. RNS suppression by Candida spp. correlated with virulence in zebrafish in vivo, suggesting RNS suppression is important for Candida spp. pathogenesis in human disease.
Hif-1α is a potential host directed therapy (HDT) target, known to increase neutrophil RNS production in bacterial infection. However, the role of Hif-1α is poorly characterised in C. albicans infections. Hif-1α stabilisation protected against C. albicans infection in zebrafish in vivo, via a neutrophil-mediated, RNS-dependent mechanism, rescuing neutrophil RNS levels after C. albicans infection. Combination of Hif-1α with antifungals had an additive effect on zebrafish survival and clearance of C. albicans infection. Hence, Hif-1α is a potential target for a HDT for C. albicans infections.
This thesis demonstrated C. albicans suppression of neutrophil RNS in vivo, a potentially important strategy in Candida pathogenesis, and highlighted the potential of targeting if-1α and RNS in HDTs against C. albicans infections.