Understanding Immunomodulation by Candida albicans

了解白色念珠菌的免疫调节作用

基本信息

批准号：
7634500
负责人：
Michael C Lorenz
金额：
$ 18.75万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-06-15 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7634500
关键词：
Affect Amino Acids Anabolism Animals Antifungal Agents Arginine Biological Blood Candida Candida albicans Candidiasis Carbohydrates Catheters Cell Communication Cells Cellular Immunity Chemicals Chemotaxis Complex Data Defect Diagnosis Disease Dissection Disseminated candidiasis Elements Enzymes Equilibrium Essential Amino Acids Genes Genetic Genomics Goals Gram-Negative Bacteria Heating Hematogenous High Pressure Liquid Chromatography Human Immune Immune system Implant In Vitro Incidence Infection Intervention Libraries Mammals Medical Medical Device Metabolic Metabolic Pathway Molecular Genetics Mutation Mycoses NOS2A gene Nature Neutropenia Nitric Oxide Nosocomial Infections Nucleotides Operative Surgical Procedures Organism Pathogenesis Pathway interactions Patients Phagocytes Phagocytosis Physical activity Process Production Protocols documentation Regulation Regulatory Element Role Scheme Series Serum Severities Systemic disease Testing Time Transcript Trauma analog antimicrobial base biological adaptation to stress cell type chemotherapy cytokine deletion analysis design dimethylarginine fighting fitness fungus gene induction human NOS2A protein immune function immunoregulation implantable device in vivo inhibitor/antagonist interest macrophage member mortality mutant neutrophil novel pathogen promoter research study response small molecule theories transcription factor

项目摘要

DESCRIPTION (provided by applicant): Candida albicans is both a ubiquitous part of the mammalian commensal flora and the most common systemic fungal pathogen of humans. Systemic disease is the fourth most common nosocomial infection and is associated with a ~40% mortality, due both to the severity of the infection and current inadequacies in diagnosis and treatment. Systemic, or disseminated, candidiasis mostly develops in patients whose innate immune system has been compromised by disease, chemotherapy, or medical intervention (surgery or implanted devices such as catheters). Thus, there is a fine line between Candida as a commensal and Candida as a pathogen and our long-term goal is to understand how this balance is maintained or disrupted to promote one state or the other. It is our premise that strengthening the immune system or weakening the fungus, even slightly, may tip this balance in favor of the patient, thus we have studied the interaction between C. albicans and cells of the innate immune system. From these studies, we have evidence that C. albicans secretes an immunomodulatory compound(s) that inhibits the release of nitric oxide (NO), a key antimicrobial and immunomodulatory compound, from macrophages. We have begun to characterize this inhibitor and have found that it is small, hydrophilic, heat-stable, and is not carbohydrate-based; one aim of this proposal is to identify this compound. In doing so, we have been aided by a series of genomic experiments that have defined the extensive and complex transcriptional response of C. albicans to phagocytosis by macrophages. One of the most surprising findings is an induction of the arginine biosynthesis pathway in its entirety. No other nucleotide or amino acid pathway is induced, making this a specific and unique response. In addition to being an essential amino acid, arginine is also the substrate for production of NO by the inducible Nitric Oxide Synthase (NOS2 or iNOS). Analogs of arginine inhibit iNOS; one such analogue has been shown to greatly reduce the anti-Candida activity of neutrophils. These arginine analogs fit our preliminary chemical characterization of the C. albicans-derived inhibitor. Thus, our central hypothesis is that C. albicans has co- opted the arginine biosynthesis pathway to produce an iNOS inhibitor, related to arginine, that promotes survival and pathogenesis of this organism. The experiments proposed here will test this hypothesis and identify the inhibitory compound. Serious fungal infections, caused mostly by Candida species, are increasingly common and severe. These affect mostly patients already debilitated by other medical treatments or illnesses and suggest that strengthening these patients' immune system would help fight these infections. We present data here that indicates that the fungus itself may be actively impairing the immune system and propose to characterize how this process occurs with the hope of eventually counteracting this ability.

描述（由申请人提供）：白色念珠菌既是哺乳动物共生菌群的无处不在的部分，也是人类最常见的系统真菌病原体。全身性疾病是第四大最常见的医院感染，由于感染的严重程度和诊断和治疗中当前的不足程度而与约40％的死亡率有关。全身性或传播的念珠菌病主要在天生的免疫系统受到疾病，化学疗法或医疗干预（手术或植入器械（例如导管）损害的患者中。因此，作为病原体的念珠菌和念珠菌作为念珠菌之间存在细微的界限，而我们的长期目标是了解如何维持或破坏这种平衡以促进一个州或另一个州。我们的前提是增强免疫系统或削弱真菌，甚至可能会稍微削弱这种平衡，以支持患者，因此我们研究了白色念珠菌与先天免疫系统的细胞之间的相互作用。从这些研究中，我们有证据表明白色念珠菌分泌一种免疫调节化合物，该化合物抑制了一氧化氮（NO）的释放，这是一种关键的抗菌和免疫调节化合物，从巨噬细胞中释放出来。我们已经开始表征这种抑制剂，并发现它是小的，亲水的，热稳定的，不是基于碳水化合物的。该提案的目的之一是确定该化合物。这样一来，我们得到了一系列基因组实验的帮助，这些实验定义了白色念珠菌对巨噬细胞吞噬作用的广泛而复杂的转录反应。最令人惊讶的发现之一是对精氨酸生物合成途径的全部诱导。没有诱导其他核苷酸或氨基酸途径，这使得这是特定而独特的响应。除了必需的氨基酸外，精氨酸还是可诱导型一氧化氮合酶（NOS2或INOS）生产NO的底物。精氨酸抑制iNOS的类似物；一种类似物已被证明可大大降低中性粒细胞的抗candiDA活性。这些精氨酸类似物符合我们的白色念珠菌抑制剂的初步化学特征。因此，我们的中心假设是白色念珠菌已经选择了精氨酸生物合成途径，以产生与精氨酸有关的iNOS抑制剂，从而促进了这种生物体的生存和发病机理。这里提出的实验将检验该假设并确定抑制性化合物。严重的真菌感染主要由念珠菌物种引起，越来越普遍且严重。这些影响主要是患者已经被其他药物或疾病衰弱的患者，并表明加强这些患者的免疫系统将有助于对抗这些感染。我们在这里提供的数据表明，真菌本身可能正在积极损害免疫系统，并建议表征该过程的发生方式，希望最终抵消这种能力。