Investigating the function of macrophages in the efficacy of anti-fungal drugs in larval zebrafish

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Project Summary/Abstract Fungal pathogens cause life-threatening disease in immuno-compromised patients, with more than 2 million people affected world-wide each year. Anti-fungal drugs that are used in the clinic to treat patients are ineffective, even though these drugs work well against fungi in a petri dish. The overarching goal of the proposed research is to increase the efficacy of these drugs inside of living organisms. The larval zebrafish is an ideal host in which to tackle this problem. Excellent live imaging and genetic tools are available, the immune systems of zebrafish and humans are largely conserved, and fungal infection models in zebrafish recapitulate pathogenesis in humans. Preliminary data indicates that synergy between the anti-fungal drug voriconazole and macrophages in vivo increases killing of the fungal pathogen Aspergillus fumigatus. I propose to identify genes and pathways in macrophages that are modulated by azole treatment and that promote azole-mediated fungal killing. First, I will focus on known cell biological pathways involved in pathogen recognition and phagosomal killing, including pathogen recognition receptor (PRR) pathways, reactive oxygen species (ROS) generation, and phagosomal acidification. Then, I will use an unbiased RNAseq-based approach to identify unknown genes that are modulated by azole treatment. Hits from both of these approaches could be targeted in the future for adjuvant therapy to boost anti-fungal efficacy in infected hosts. Altogether, results from this proposal will identify new targets for immuno- therapeutic adjuvant therapy to increase the efficacy of anti-fungal treatment in patients.