Genetics and visualization of innate host response to C. albicans infection in vi

体外宿主对白色念珠菌感染的先天反应的遗传学和可视化

基本信息

批准号：
8289894
负责人：
Robert T Wheeler
金额：
$ 42.16万
依托单位：
UNIVERSITY OF MAINE ORONO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-01 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8289894
关键词：
Ablation Address Affect Animals Blood Circulation Candida Candida albicans Catheterization Cause of Death Cells Chronic Granulomatous Disease Communicable Diseases Controlled Environment Cues Data Development Disease Epidemiology Fishes Genes Genetic Germination Goals Growth Human Image Imagery Immune Immune response Immunity Immunocompromised Host In Vitro Individual Infection Intravenous Investigation Laboratories Lead Life Link Longitudinal Studies Medical Methodology Methods Modeling Molecular Morbidity - disease rate Morphogenesis Mus Mutation Mycoses Natural Immunity Neutropenia Nosocomial Infections Organ Transplantation Outcome Oxidases Pathogenesis Pathway interactions Phagocytes Play Positioning Attribute Procedures Publishing Resolution Rodent Role Screening procedure Side Signal Transduction Site Staging System Technology Temperature Testing Therapeutic Time Tissues Transgenic Organisms Translating United States Virulence Work Yeasts Zebrafish alternative treatment attributable mortality base candidemia chemotherapy dimorphism fungus high throughput screening human disease in vivo innate immune function macrophage microbial mortality mutant novel novel therapeutic intervention pathogen patient population prevent receptor research study response

项目摘要

DESCRIPTION (provided by applicant): Candidemia is the 4th most common nosocomial infection, and leads to disproportionate mortality. Candida albicans is a ubiquitous commensal and the most frequent cause of fungal disease in humans. Disseminated bloodstream candidemia carries a >30% attributable mortality and is associated with chemotherapy-induced neutropenia, organ transplantation, primary genetic defects such as chronic granulomatous disease, and medical procedures such as intravenous catheterization that provide direct access to the bloodstream. Human epidemiology and mouse experiments have demonstrated that innate immune function is the primary barrier against disseminated disease, yet the role of macrophages in response and clearance of disease is still unclear. Unfortunately, technical constraints have limited our ability to test the roles of macrophages in their natural context of infection. The relatively weak capacity of isolated macrophages to destroy C. albicans in the absence of matrix and soluble cues has led to the idea that they play a marginal role limiting infection but could promote dissemination of disease among tissues. However, our recent non-invasive imaging, using a new transparent model of disseminated Candida-zebrafish infection, indicates that macrophages in their natural context have an enhanced ability to limit proliferation and germination of C. albicans. We hypothesize that macrophages limit filamentous growth of C. albicans but promote dissemination of infection throughout the body. We will exploit the zebrafish infection model to determine the role of macrophages in limiting fungal proliferation and promotion of dissemination using intravital real-time imaging, gene knockdown, targeted cell ablation, and fungal mutants. Transgenic fish with marked macrophages will be used to follow individual fungal-phagocyte interactions in vivo, and we will ablate and perturb macrophages to determine their role in regulating fungal morphogenetic switching, proliferation and dissemination. The proposed experiments will test basic questions of innate immunity that have been intractable in mammalian models by exploiting the advantages of the transparent zebrafish model. The results of the proposed experiments will yield a more complete basic understanding of the mechanisms underlying innate immunity to candidemia and set the stage for targeted screening for novel host and pathogen pathways regulating these macrophage activities. The discovery of mechanisms underlying macrophage activity during fungal infection has the potential to lead to new therapeutic interventions. PUBLIC HEALTH RELEVANCE: Infectious diseases affect humans worldwide and cause significant mortality and morbidity in the United States. Current methods to control fungal disease are inadequate, especially in the immunocompromised patient population, so it is critical to investigate alternative treatments. A long-term goal of this investigation involves leveraging basic information about host-pathogen interaction to develop therapeutics to treat fungal disease.

描述（由申请人提供）：候选血症是第四大常见的医院感染，导致死亡率不成比例。白色念珠菌是无处不在的共生，也是人类真菌疾病的最常见原因。传播的血液念珠菌携带> 30％的可归因死亡率，并且与化学疗法诱导的中性粒细胞减少症，器官移植，主要遗传缺陷（例如慢性肉芽肿性疾病）以及诸如静脉内导管等医疗程序有关，可直接进入血液群。人类流行病学和小鼠实验表明，先天免疫功能是反对传播疾病的主要障碍，但是巨噬细胞在疾病中的作用和清除疾病仍然尚不清楚。不幸的是，技术约束限制了我们测试巨噬细胞在自然感染中的作用的能力。在没有基质和可溶性提示的情况下，孤立的巨噬细胞破坏白色念珠菌的相对较弱的能力导致了这样的想法，即它们在限制感染的边缘角色中起着边缘作用，但可以促进组织之间疾病的传播。但是，我们最近使用新的透明念珠菌感染的新透明模型的非侵入性成像，表明巨噬细胞在其自然情境中具有限制增殖的能力增强和白色念珠菌的发芽。我们假设巨噬细胞限制了白色念珠菌的丝状生长，但促进了整个体内感染的传播。我们将利用斑马鱼感染模型来确定巨噬细胞在限制真菌增殖中的作用，并使用插入的实时成像，基因敲低，靶向细胞消融和真菌突变体促进传播。具有明显巨噬细胞的转基因鱼将用于遵循体内的单个真菌 - 光细胞相互作用，我们将消融和扰动巨噬细胞确定它们在调节真菌形态发生，增殖和传播中的作用。提出的实验将通过利用透明的斑马鱼模型的优势来测试哺乳动物模型中先天免疫的基本问题。提出的实验的结果将对对候选血症的先天免疫力的基本机制产生更完整的理解，并为调节这些巨噬细胞活性的新型宿主和病原体途径的靶向筛查奠定了基础。在真菌感染过程中发现巨噬细胞活性的机制的发现有可能导致新的治疗干预措施。公共卫生相关性：传染病影响全世界的人类，并在美国引起重大死亡率和发病率。当前控制真菌疾病的方法不足，尤其是在免疫功能低下的患者人群中，因此研究替代治疗至关重要。这项调查的长期目标是利用有关宿主病原体相互作用的基本信息来开发治疗真菌疾病的治疗剂。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Candidalysin is a fungal peptide toxin critical for mucosal infection.

DOI：
10.1038/nature17625
发表时间：
2016-04-07
期刊：
Nature
影响因子：
64.8
作者：
Moyes DL;Wilson D;Richardson JP;Mogavero S;Tang SX;Wernecke J;Höfs S;Gratacap RL;Robbins J;Runglall M;Murciano C;Blagojevic M;Thavaraj S;Förster TM;Hebecker B;Kasper L;Vizcay G;Iancu SI;Kichik N;Häder A;Kurzai O;Luo T;Krüger T;Kniemeyer O;Cota E;Bader O;Wheeler RT;Gutsmann T;Hube B;Naglik JR
通讯作者：
Naglik JR

Polyclonal anti-Candida antibody improves phagocytosis and overall outcome in zebrafish model of disseminated candidiasis.