Impact of Candida Oxylipins on Host Immunity and Fungal Biology

氧脂假丝酵母对宿主免疫和真菌生物学的影响

• 批准号: 8109941
• 负责人: Mairi C Noverr
• 金额: $ 31.2万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-15 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8109941
• 关键词: Antifungal Agents; Arachidonic Acids; Area; Biology; Candida; Candida albicans; Candidiasis; Cell Communication; Cells; Chronic; Core Facility; Data; Dendritic Cells; Dendritic cell activation; Development; Dinoprostone; Disease; Eicosanoid Production; Eicosanoids; Ensure; Environment; Enzymes; Exhibits; Fatty Acids; Gastrointestinal tract structure; Genes; Genetic; Goals; Health; Human; Hyphae; Immune; Immune response; Immune system; Immunity; In Vitro; Infection; Intervention; Invaded; Knockout Mice; Knowledge; Leukotrienes; Lipid Biochemistry; Lipids; Methods; Microbe; Microbial Biofilms; Microbiology; Modeling; Molecular; Molecular Biology; Morphogenesis; Mucosal Immunity; Mutagenesis; Mycoses; Outcome; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Plants; Predisposition; Production; Prostaglandin Antagonists; Prostaglandin Production; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Prostaglandins A; Public Health; Reporting; Research; Role; Signal Transduction; Signaling Molecule; Surface; Systemic infection; Testing; Tissues; Vaccination; Virulence; Work; Yeasts; base; experience; fungus; immunoregulation; in vitro Assay; in vivo; in vivo Model; inhibitor/antagonist; mutant; new therapeutic target; novel; novel strategies; novel therapeutics; overexpression; pathogen; prevent

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE 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.

描述（由申请人提供）：机会性真菌病原体白色念珠菌产生免疫调节性氧脂素，其与宿主类二十烷酸（前列腺素和白三烯）发生功能性交叉反应，而宿主类二十烷酸是先天性和适应性免疫反应的有效调节剂。此外，念珠菌可以在宿主脂肪酸前体存在的情况下产生真正的宿主类二十烷酸。尽管宿主和酵母都能产生相似的信号分子，但氧脂素在宿主-病原体相互作用中的作用尚未得到充分表征，真菌氧脂素生物合成酶也尚未被鉴定。缺乏此类知识是一个重要问题，因为它限制了针对病原真菌中这些途径的新型治疗策略的开发，其中大多数病原真菌产生氧脂质。这项研究的长期目标是表征念珠菌在宿主中的持久性和免疫调节机制。该提案的目的是确定真菌氧脂素和宿主类二十烷酸在影响念珠菌生物学和宿主免疫方面的作用。我们的中心假设是，真菌和宿主产生的氧脂素对于调节真菌的微生物学和有利于慢性感染或持续存在的宿主-病原体相互作用至关重要。拟议研究的基本原理是，确定宿主和真菌氧脂素在宿主-微生物相互作用中的作用，将提供有关念珠菌影响免疫机制的关键信息，并促进开发用于治疗和控制真菌感染的新型药理干预措施。第一个具体目标是使用分子方法（过度表达和定向诱变）来鉴定和表征参与氧脂素产生和发病机制的念珠菌基因。将使用体外测定来分析突变体，以检查形态发生和生物膜形成以及念珠菌病的体内模型。第二个具体目标是确定真菌和宿主氧脂素对念珠菌生物学（形态发生和生物膜形成）和抗真菌药物敏感性的影响。第三个具体目标是确定真菌和宿主氧脂素对宿主-病原体相互作用的下游影响，无论是在体内还是与树突状细胞（DC）。体内分析将涉及在全身和粘膜感染模型中使用前列腺素抑制剂和环氧合酶敲除小鼠（负责前列腺素产生的宿主酶）。 DC 分析将涉及研究氧脂质对体外 DC 成熟和激活以及体内 DC 疫苗接种期间的影响。我们对这一研究领域的贡献预计将是详细了解氧脂素的产生方式及其在念珠菌发病机制和生物学中的作用。这一贡献意义重大，因为它有望提供开发药理学策略所需的知识，这些策略专门针对参与这些免疫调节真菌生物活性脂质生产的生物合成途径，并提供有关氧脂素和类二十烷酸在宿主与病原体相互作用过程中的作用的信息。公共卫生相关性 这项工作的结果将对念珠菌相关疾病的公共卫生产生积极影响，因为氧脂质途径有望提供新的治疗靶点。这些研究将对了解所有病原真菌微生物的毒力策略具有重要意义，其中大多数病原真菌微生物产生氧脂质。更重要的是，用类二十烷酸抑制剂靶向真菌氧脂素途径是一种可用于调节感染过程的新策略。这些药物有可能干扰真菌和宿主，阻止真菌形态发生、氧脂素产生和活力，并影响免疫反应。