Genetic determinants of bacterial-drug synergy against Candida

对抗念珠菌的细菌-药物协同作用的遗传决定因素

基本信息

批准号：
10584713
负责人：
Robert T Wheeler
金额：
$ 43.51万
依托单位：
UNIVERSITY OF MAINE ORONO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-11-18 至 2025-10-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10584713
关键词：
Address Affect Antifungal Agents Automobile Driving Bacteria Basic Science Calcineurin Candida Candida albicans Candidate Disease Gene Cells Cessation of life Clinical Communicable Diseases Communication Complex Cystic Fibrosis Data Disease Drug Efflux Drug Synergism Drug Tolerance Elements Environment Europe Failure Fluconazole Future Genes Genetic Determinism Goals Gram-Negative Bacteria Homeostasis Hospitalization Human Immune Immune response Immunocompromised Host In Vitro Infection Inflammatory Investigation Iron Libraries Link Measures Methodology Methods Microbe Modeling Morbidity - disease rate Opportunistic Infections Pathway interactions Patients Phagocytosis Pharmaceutical Preparations Pharmacotherapy Play Predisposition Pseudomonas Pseudomonas aeruginosa Publishing Research Research Proposals Role Signal Transduction Starvation Sterols Stress Testing Therapeutic Translating Translational Research United States Vesicle Virulence Virulence Factors Work Zebrafish alternative treatment antagonist blocking factor co-infection defined contribution fungicide fungus genetic analysis genetic approach in vivo intravital imaging microbial genomics mortality mutant neutrophil novel opportunistic pathogen pathogen pathogenic fungus patient population response screening serial imaging success synergism trafficking ventilation

Address Affect Antifungal Agents Automobile Driving Bacteria Basic Science Calcineurin Candida Candida albicans Candidate Disease Gene Cells Cessation of life Clinical Communicable Diseases Communication Complex Cystic Fibrosis Data Disease Drug Efflux Drug Synergism Drug Tolerance Elements Environment Europe Failure Fluconazole Future Genes Genetic Determinism Goals Gram-Negative Bacteria Homeostasis Hospitalization Human Immune Immune response Immunocompromised Host In Vitro Infection Inflammatory Investigation Iron Libraries Link Measures Methodology Methods Microbe Modeling Morbidity - disease rate Opportunistic Infections Pathway interactions Patients Phagocytosis Pharmaceutical Preparations Pharmacotherapy Play Predisposition Pseudomonas Pseudomonas aeruginosa Publishing Research Research Proposals Role Signal Transduction Starvation Sterols Stress Testing Therapeutic Translating Translational Research United States Vesicle Virulence Virulence Factors Work Zebrafish alternative treatment antagonist blocking factor co-infection defined contribution fungicide fungus genetic analysis genetic approach in vivo intravital imaging microbial genomics mortality mutant neutrophil novel opportunistic pathogen pathogen pathogenic fungus patient population response screening serial imaging success synergism trafficking ventilation

展开

项目摘要

Opportunistic infections in hospitalized patients remain an important unsolved clinical problem, leading to an estimated 230,000 annual deaths in the US and Europe. Two of the most important opportunistic pathogens are the fungus Candida albicans and the gram-negative bacterium Pseudomonas aeruginosa. They are frequently co-isolated in ventilated patients and in cystic fibrosis, where co-association is linked to exacerbated disease. Drug treatment of these two opportunistic infections is often problematic, and we hypothesize that some of these failures are due to the impact of microbe-microbe and microbe-immune interactions during co- infection. The proposed research seeks to address this major gap in our understanding to define whether the complexity of co-infection demands a different view of therapeutic strategy. Our overall goal is to understand how Pseudomonas-Candida interactions affect virulence and therapeutic success. We recently found that the antifungal drug fluconazole (FLC) is much more effective and fungicidal against C. albicans in the presence of P. aeruginosa, both in vitro and in vivo. In this proposal, our driving hypothesis is that specific bacterial virulence factors block fungal tolerance to FLC. We hypothesize that iron starvation and calcineurin signaling are two key elements in this synergy, based on our preliminary data as well as published work connecting iron homeostasis and calcineurin to drug tolerance. Leveraging the power of intravital imaging in zebrafish together with microbial genomics will enable our genetic analyses of bacteria and fungi in the context of treatment and infection. We propose to uncover novel bacterial and fungal contributors to P. aeruginosa-FLC synergy against C. albicans through a complementary candidate gene/unbiased screening strategy in vitro (Aim 1). We will then utilize longitudinal intravital imaging of fungi, bacteria, and innate immune cells in the transparent zebrafish to test the relevance of these mechanisms and the innate immune contributions to fungal therapy during co-infection in the vertebrate host (Aim 2). The findings from these proposed studies will yield a network of bacterial and fungal pathways that operate in vivo to regulate drug susceptibility. This proposal has the potential to open up a new front in our study of how communication between bacteria and fungi during infection regulates drug susceptibility. While this is a basic science research proposal that will reveal new cross-kingdom interactions during infection, the focus on antifungal treatment also has significant potential for informing future translational research.

住院患者的机会性感染仍然是一个重要的未解决的临床问题，导致美国和欧洲估计每年230,000例死亡。最重要的两个机会病原体是真菌白色念珠菌和革兰氏阴性细菌铜绿假单胞菌。他们是经常在通风患者和囊性纤维化中共隔离，在共同关联与恶化有关疾病。这两种机会感染的药物治疗通常是有问题的，我们假设这些失败中的一些是由于微型微生物和微生物 - 免疫相互作用的影响。感染。拟议的研究试图解决我们理解的这一主要差距，以定义共同感染的复杂性需要不同的治疗策略观点。我们的总体目标是了解假单胞菌的相互作用如何影响毒力和治疗性成功。我们最近发现，抗真菌药物氟康唑（FLC）更有效和杀真菌在体外和体内的铜绿假单胞菌存在下，针对白色念珠菌。在此提案中，我们的驾驶假设是特定的细菌毒力因子阻止了对FLC的真菌耐受性。我们假设铁基于我们的初步数据作为将铁稳态和钙调神经酶与药物耐受性联系起来的发表工作。利用斑马鱼和微生物基因组学中的静脉成像将使我们对细菌和细菌的遗传分析在治疗和感染的背景下真菌。我们建议发现新颖的细菌和真菌贡献者通过互补的候选基因/公正体外筛选策略（AIM 1）。然后，我们将利用真菌，细菌和透明斑马鱼中的先天免疫细胞测试这些机制和先天性的相关性脊椎动物宿主共感染期间对真菌疗法的免疫贡献（AIM 2）。这些拟议的研究的发现将产生一个细菌和真菌途径网络体内调节药物敏感性。该提议有可能在我们的研究中开辟一个新的阵线感染期间细菌与真菌之间的通信调节药物敏感性。虽然这是一个基本科学研究建议将揭示感染期间新的跨王国相互作用抗真菌治疗也有巨大的潜力来告知未来的翻译研究。