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）：念珠菌血症是第四大最常见的医院感染，并导致不成比例的死亡率。白色念珠菌是一种普遍存在的共生菌，也是人类真菌疾病的最常见原因。播散性血流念珠菌血症的死亡率>30%，并与化疗引起的中性粒细胞减少症、器官移植、慢性肉芽肿性疾病等原发性遗传缺陷以及直接进入血流的静脉导管插入术等医疗程序有关。人类流行病学和小鼠实验已证明先天免疫功能是抵抗播散性疾病的主要屏障，但巨噬细胞在疾病反应和清除中的作用仍不清楚。不幸的是，技术限制限制了我们测试巨噬细胞在自然感染环境中的作用的能力。在缺乏基质和可溶性线索的情况下，分离的巨噬细胞破坏白色念珠菌的能力相对较弱，这导致人们认为它们在限制感染方面发挥边缘作用，但可能促进疾病在组织之间的传播。然而，我们最近的非侵入性成像，使用一种新的透明的播散性念珠菌-斑马鱼感染模型，表明巨噬细胞在自然环境中具有增强的限制增殖的能力和白色念珠菌的发芽。我们假设巨噬细胞限制白色念珠菌的丝状生长，但促进感染在全身的传播。我们将利用斑马鱼感染模型，通过活体实时成像、基因敲低、靶向细胞消融和真菌突变体来确定巨噬细胞在限制真菌增殖和促进传播方面的作用。带有标记巨噬细胞的转基因鱼将用于跟踪体内单个真菌-吞噬细胞的相互作用，我们将消融和扰乱巨噬细胞以确定它们在调节真菌形态发生转换、增殖和传播中的作用。拟议的实验将利用透明斑马鱼模型的优势来测试在哺乳动物模型中难以解决的先天免疫的基本问题。所提出的实验结果将使人们对念珠菌血症先天免疫机制有更完整的基本了解，并为有针对性地筛选调节这些巨噬细胞活性的新宿主和病原体途径奠定基础。真菌感染期间巨噬细胞活性的潜在机制的发现有可能带来新的治疗干预措施。公共卫生相关性：传染病影响全世界人类，并在美国造成显着的死亡率和发病率。目前控制真菌病的方法不足，特别是在免疫功能低下的患者群体中，因此研究替代疗法至关重要。这项研究的长期目标涉及利用宿主与病原体相互作用的基本信息来开发治疗真菌疾病的疗法。

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.