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: 7900418
• 负责人: Mairi C Noverr
• 金额: $ 31.52万
• 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 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7900418
• 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; 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; public health relevance

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)：机会真菌病原体白色念珠菌产生免疫调节氧脂，与宿主二十烷类化合物(前列腺素和白三烯)发生功能交叉反应，这是天然和获得性免疫反应的有效调节器。此外，假丝酵母可以在宿主脂肪酸前体存在的情况下产生真正的宿主二十烷类化合物。尽管宿主和酵母菌都能产生相似的信号分子，但氧化脂在宿主-病原菌相互作用中的作用还没有得到充分的表征，真菌氧化脂生物合成酶也没有被鉴定。缺乏这样的知识是一个重要的问题，因为它限制了针对病原真菌中这些途径的新治疗策略的开发，其中大多数病原真菌会产生氧磷脂。本研究的长期目标是研究假丝酵母菌在宿主中的持久性和免疫调节机制。这项建议的目的是确定真菌氧化脂和宿主二十烷类化合物在影响念珠菌生物学和宿主免疫中的作用。我们的中心假设是，真菌和宿主产生的氧磷脂在调节真菌的微生物学和宿主与病原体的相互作用有利于慢性感染或持久性方面是至关重要的。这项研究的基本原理是，确定宿主和真菌氧化脂在宿主-微生物相互作用中的作用将提供有关念珠菌影响免疫的机制的关键信息，并有助于开发治疗和控制真菌感染的新的药理干预措施。第一个具体目标将是利用分子方法--超量表达和定向突变--识别和表征参与氧脂产生和发病的念珠菌基因。将使用体外试验对突变株进行分析，以检查念珠菌病的形态发生和生物膜形成以及体内模型。第二个具体目标是确定真菌和宿主氧脂对念珠菌生物学(形态发生和生物膜形成)和抗真菌药物敏感性的影响。第三个具体目标将是确定真菌和宿主氧脂在体内和与树突状细胞(DC)相互作用中对宿主-病原体相互作用的下游影响。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基因敲除小鼠(负责前列腺素产生的宿主酶)。DC分析将包括研究氧脂对体外和体内DC疫苗接种过程中DC成熟和激活的影响。我们对这一研究领域的贡献有望是详细了解氧脂是如何产生的，以及它们在念珠菌的发病机制和生物学中的作用。这一贡献是重要的，因为它有望提供所需的知识，以开发专门针对这些免疫调节真菌生物活性脂质产生的生物合成途径的药物策略，并提供关于氧磷脂和二十烷类化合物在宿主-病原体相互作用中的作用的信息。这项工作的公共卫生相关性结果将在治疗念珠菌相关疾病方面对公共卫生产生积极影响，因为氧化脂质途径有望提供新的治疗靶点。这些研究将对理解所有病原真菌的毒力策略具有重要意义，其中大多数病原真菌会产生氧磷脂。更重要的是，用二十烷类化合物抑制真菌氧化脂质途径是一种新的策略，可以用来调节感染的过程。这些药物有可能同时干扰真菌和宿主，阻止真菌的形态发生、氧磷脂的产生和活性，并影响免疫反应。