How Does Nlrx1 regulate fungal killing and immune signaling during pulmonary infection

Nlrx1如何调节肺部感染期间的真菌杀灭和免疫信号传导

• 批准号: 9979165
• 负责人: Shiv Dutt Kale
• 金额: $ 24.03万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-06 至 2020-06-13
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9979165
• 关键词: Acute; Allergic Bronchopulmonary Aspergillosis; Alveolar; Antifungal Agents; Aspergillus fumigatus; Asthma; Bacteria; Biological Assay; Cell Line; Cell membrane; Cells; Centers for Disease Control and Prevention (U.S.); Chronic; Clinical; Data; Defense Mechanisms; Development; Diagnostic; Epithelial Cells; Excision; Fungal Drug Resistance; Fungal Proteins; Generations; Genes; Germination; Growth; Human; Hyphae; IL8 gene; Immune; Immune response; Immune signaling; Immune system; Immunocompetent; Immunocompromised Host; In Vitro; Incidence; Infection; Inflammation; Inflammatory; Inhalation; Interleukin 6 Receptor; Interleukin-6; Knock-out; Leukocytes; Lung; Lung diseases; Lung infections; Malignant Neoplasms; Mediating; Metabolism; Modeling; Morphology; Multi-Drug Resistance; Mus; Mycoses; Neutrophil Infiltration; Organoids; Pathway interactions; Pattern; Population; Process; Production; Proteins; Reactive Oxygen Species; Recombinants; Regulation; Resistance; Respiratory System; Respiratory Tract Infections; Rest; Role; Series; Signal Transduction; Signal Transduction Pathway; Structure of parenchyma of lung; Testing; Therapeutic; Tissues; Ubiquitination; United States; United States National Institutes of Health; Virus; airway epithelium; base; chemokine; clinically relevant; combat; comparative genomics; cytokine; dectin 1; defense response; design; differential expression; experimental study; extracellular; fungus; gain of function; human pathogen; immunosuppressed; in vivo; insight; loss of function; mortality; mouse model; neutrophil; novel; novel strategies; novel therapeutics; pathogenic fungus; personalized approach; prevent; protein expression; receptor; recruit; respiratory; response; transcriptome sequencing

PROJECT SUMMARY Invasive fungal infections caused by a variety of fungal pathogens are on the rise in the United States and globally. Alarmingly, a growing number of these clinical isolates are resistant to anti-fungal treatments. There have been recent calls by the CDC and NIH for the development of novel strategies to develop diagnostics and therapeutics to combat fungal infections. Invasive infections of the respiratory system by the clinically relevant fungus Aspergillus fumigatus occur in a wide variety of immunosuppressed populations and can be associated with very high mortality rates. Strains of A. fumigatus resistant to common anti-fungals are also on the rise. This study aims to dissect a component of the host immune system (known commonly as Nlrx1) that is capable of amplifying the recruitment of important white blood cell populations (neutrophils), and regulating killing of fungal conidia and hyphae by airway epithelial cells (the first cells in contact with inhaled fungi). The applicant has shown that loss of Nlrx1 results in increased fungal growth as well as host mortality suggesting its function is critical for immune signaling as well as cell specific defense responses. How Nlrx1 regulates these processes is unknown. The preliminary data suggests this process occurs through non-oxidative mechanisms. Specific Aim 1 is designed to identify anti-fungal proteins that are generated and secreted by airway epithelial in a manner dependent upon Nlrx1. The expression of these proteins is thought to be mitigated in Nlrx1 deficient cells, which is a reasonable explanation for the enhanced fungal germination and growth observed in vivo and in vitro. Completion of Aim 1 will provide the identification and characterization of novel host derived anti-fungal proteins that reduce fungal germination and hyphae growth in vitro and in vivo. Aim 2 is designed to determine if expression of Nlrx1 in lung tissue, mediates enhanced fungal growth and immune signaling observed in whole body knockouts. This will be done through generation of lung specific knockouts of Nlrx1 via available Cre-lox mice. Aim 2 will also provide mechanistic insight into how Nlrx1interacts with different cell membrane receptors that sense fungi. Completion of this proposal will provide novel insight into how lung tissue Nlrx1 regulates both oxidative and non-oxidative defense mechanisms in response to conidia and hyphae.

项目摘要 由多种真菌病原体引起的侵袭性真菌感染在美国和全球范围内呈上升趋势。 令人担忧的是，越来越多的这些临床分离株对抗真菌治疗具有耐药性。最近有电话 疾病预防控制中心和国家卫生研究院开发新的战略，发展诊断和治疗，以打击真菌 感染.临床相关真菌烟曲霉对呼吸系统的侵袭性感染发生在 广泛的免疫抑制人群，并可能与非常高的死亡率有关。株供试菌烟曲霉 对普通抗真菌药物产生抗药性的人也在增加。本研究旨在剖析宿主免疫系统的一个组成部分 （通常称为Nlrx 1），其能够扩增重要的白色血细胞群体的募集 （嗜中性粒细胞），并通过气道上皮细胞（第一个接触的细胞）调节真菌分生孢子和菌丝的杀伤。 吸入真菌）。申请人已经表明，Nlrx 1的缺失导致真菌生长增加以及宿主死亡率增加 提示其功能对于免疫信号传导以及细胞特异性防御反应是关键的。Nlrx 1如何调节 这些过程是未知的。初步数据表明，这一过程通过非氧化机制发生。具体 目的1旨在鉴定气道上皮以依赖性方式产生和分泌的抗真菌蛋白 在Nlrx 1上。这些蛋白质的表达被认为在Nlrx 1缺陷细胞中减轻，这是合理的解释。 解释了在体内和体外观察到的增强的真菌萌发和生长。目标1的完成将提供 鉴定和表征新的宿主来源的抗真菌蛋白，其减少真菌萌发和菌丝 体外和体内生长。目的2：确定Nlrx 1在肺组织中的表达是否介导增强的真菌感染， 在全身敲除中观察到生长和免疫信号传导。这将通过生成肺特异性 通过可用的Cre-lox小鼠敲除Nlrx 1。目标2还将提供Nlrx 1如何与 感受真菌的不同细胞膜受体。该提案的完成将提供新的见解如何肺 组织Nlrx 1调节响应分生孢子和菌丝的氧化和非氧化防御机制。