Control of Type I Interferon Production in Response to Candida

Univ Of Massachusetts Med Sch Worcester, Worcester MA

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Abstract

PROJECT SUMMARY Invasive bloodstream infection by the fungal pathogen Candida spp. remains one of the most common infections in hospitalized patients, carrying a mortality rate of over 50%. Despite the current antifungal arsenal, these mortality rates have not decreased, especially with the emergence of multi-drug resistant strains of Candida. Human SNPs implicate the type I interferon (IFN) pathway with increased susceptibility to candidemia. Interestingly, mice deficient in components of the type I IFN cGAS-STING pathway were more resistant to bloodstream Candida albicans infection. We recently established that DNA contained in C. albicans extracellular vesicles (EVs) potently activates the cGAS-STING pathway as evidenced by increased IFN stimulated genes, viperin production, IFN-β secretion, and phosphorylation of key downstream proteins (i.e., TBK1 and IRF3). The mechanism and functional consequences of how this pathway contributes to the host response to Candida infection remain unknown. Our findings regarding EVs were not exclusive to C. albicans but also expanded to other fungi (e.g., Candida auris). We revealed that STING activation occurs independently of TLR9 and Dectin-1 signaling. Additionally, knockdown or blockage of the cGAS functional site for TREX1, a key exonuclease that regulates the cGAS- STING pathway, elevated viperin expression in EV-stimulated macrophages. These data form the groundwork to explore further the consequences of type I IFN response in Candida infections and the basis of our long-term goal. Our overall testable hypothesis is that the magnitude of STING-IFN signaling pathway activation determines the outcome of invasive candidiasis as determined by fungal burden and survival. To address this hypothesis, we propose the following three specific aims: [1] investigate the role of viperin and TREX1 in the innate immune response to invasive candidiasis; [2] determine the impact of impairment of EV production by C. albicans on the pathogenicity of invasive candidiasis; and [3] exploit the STING pathway to induce protection against invasive candidiasis. Successful completion of the proposed studies will provide a greater understanding of type I IFN response to invasive candidiasis and may lead to novel therapeutic targets to modulate the immune response to improve clinical outcomes in patients with candidemia.