The opportunistic fungal pathogen Candida albicans produces immunomodulatory oxylipins that cross- react functionally with host eicosanoids (prostaglandins and leukotrienes), which are potent regulators of innate and adaptive immune responses. In addition, Candida can produce authentic host eicosanoids in the presence of host fatty acid precursors. Despite the fact that both the host and yeast can produce similar signaling molecules, the role of oxylipins in host-pathogen interactions has not been fully characterized nor have the fungal oxylipin biosynthetic enzymes been identified. Lack of such knowledge is an important problem, because it limits development of novel therapeutic strategies that target these pathways in pathogenic fungi, most of which produce oxylipins. The long term goal of this research is to characterize mechanisms of Candida persistence and immunomodulation in the host. The objective of this proposal is to determine the role of fungal oxylipins and host eicosanoids in influencing Candida biology and host immunity. Our central hypothesis is that production of oxylipins by both fungi and host are crucial in modulating the microbiology of the fungus and the host-pathogen interaction in favor of chronic infection or persistence. The rationale for the proposed research is that determining the role of host and fungal oxylipins in host-microbe interactions will provide key information about the mechanisms by which Candida influences immunity and facilitate development of novel pharmacological interventions for treatment and control of fungal infection. The first specific aim will be to identify and characterize Candida genes involved in oxylipin production and pathogenesis using molecular methods-both overexpression and targeted mutagenesis. Mutants will be analyzed using in vitro assays to examine morphogenesis and biofilm formation and in vivo models of candidiasis. The second specific aim will be to determine the effects of the effects of fungal and host oxylipins on Candida biology (morphogenesis and biofilm formation) and susceptibility to antifungal drugs. The third specific aim will be to determine the downstream effects of fungal and host oxylipins on host-pathogen interactions, both in vivo and with dendritic cells (DCs). In vivo analysis will involve the use of prostaglandin inhibitors and cyclooxygenase knockout mice (host enzyme responsible for prostaglandin production) during systemic and mucosal infection models. DC analysis will involve studying the effects of oxylipins on maturation and activation of DCs in vitro and during DC vaccination in vivo. Our contribution to this area of research is expected to be a detailed understanding of how oxylipins are produced and their roles in Candida pathogenesis and biology. This contribution is significant because it is expected to provide the knowledge needed to develop pharmacologic strategies that specifically target the biosynthetic pathways involved in production of these immunomodulatory fungal bioactive lipids and provide information regarding the role of oxylipins and eicosanoids during host-pathogen interactions.
Results from this work will have a positive impact on public health in terms of treating Candida-associated diseases, as oxylipin pathways are expected to provide novel therapeutic targets. These studies will have important implications for understanding virulence strategies of all pathogenic fungal microbes, most of which produce oxylipins. More importantly, targeting fungal oxylipin pathways with eicosanoid inhibitors is a novel strategy that can be used to modulate the course of an infection. These drugs have the potential to interfere with both the fungus and the host, preventing fungal morphogenesis, oxylipin production, and viability, and also influencing immune responses.
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