Host-Pneumococcal Interaction in the Lung

肺部宿主与肺炎球菌的相互作用

• 批准号: 8966696
• 负责人: Charles S Dela Cruz
• 金额: $ 41.96万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8966696
• 关键词: Address; Adult; Affect; Agonist; Antibacterial Response; Antibiotics; Apoptotic; Bacteria; Bacterial Infections; Bacterial Pneumonia; Biological Response Modifiers; Blood Circulation; CASP1 gene; CHI3L1 gene; Cause of Death; Cell Separation; Cells; Chimera organism; Chitinase; Clinical; Cre-LoxP; Data; Dendritic Cells; Development; Disease; Dopamine D2 Receptor; Drug resistance; Epithelial Cells; Etiology; Family; Health; Host Defense; Human; Hydrolase; Immune response; Immunotherapeutic agent; In Vitro; Infection; Inflammation; Inflammatory; Injury; Intensive Care Units; Interferon Type I; Interferons; Lung; Microscopy; Mind; Modality; Modeling; Mononuclear; Morbidity - disease rate; Mus; Outcome; Pathway interactions; Patients; Phagolysosome; Pneumococcal Infections; Pneumonia; Process; Production; Prognostic Marker; Proteins; Regulation; Reporting; Research; Resolution; Role; Sampling; Sepsis; Serum; Signal Transduction; Staining method; Stains; Streptococcus pneumoniae; TLR9 gene; Testing; Therapeutic; Tissues; Transfection; Translations; United States; Virus Diseases; Work; adapter protein; bone; cellular imaging; clinically relevant; clinically significant; human subject; immune activation; immunopathology; in vivo Model; insight; interferon regulatory factor-7; killings; lung injury; macrophage; mortality; mouse model; novel; novel therapeutics; pathogen; receptor; receptor binding; response; spatiotemporal; therapeutic target; tissue repair; trafficking

DESCRIPTION (provided by applicant): Bacterial pneumonia and sepsis are leading preventable causes of death in the intensive care unit and Streptococcus pneumoniae (Sp) is a major etiology. Current therapies are mostly focused on the use of antibiotics and have led to the rapid emergence of drug resistance and hypervirulent strains. A fundamental aspect of successful pathogen-host interactions is the ability to keep harmful, tissue-damaging inflammatory immune responses in check while successfully clearing the pathogen. The exaggerated morbidity and mortality seen with bacterial infection can be the result of dysregulated inflammation. There are currently no viable therapeutic modalities to augment host defense while reducing unnecessary inflammation. Further, it is poorly understood how signaling cascades converge to control host defenses while minimizing inflammatory tissue injury. With this in mind, we have identified Chitinase 3-like 1 (Chi3l1), a prototypic Chitinase-like protein of 18- glycosyl hydrolase family, to be important in this process. We find that Chi3l1 is a potent innate immune regulator elevated in patients with diseases characterized by inflammation and tissue repair. Chi3l1, along with its newly discovered receptor IL13RD2, is induced during Sp infection and is critical in antibacterial responses. The Chi3l1-IL13RD2 axis is important as a therapeutic target for controlling potentially harmful innate immune activation during bacterial infection. Our data show that the Chi3l1-IL13RD2 interaction critically dampens potentially harmful type I interferon (IFN-1) responses during infection. The absence of Chi3l1 or IL13RD2 results in heightened IFN-1s during infection associated with increased co-localization of endosomal Toll-like receptor 9 (TLR9) and interferon regulatory factor 7 (IRF7). Our overall hypothesis is that the Chi3l1-IL13RD2 dampens excessive inflammation and tissue injury by regulating IFN-1 pathway. We will test this hypothesis with the following specific aims: Specific Aim 1. Characterize the mechanisms by which Chi3l1 and its receptor IL13RD2 regulate IFN-1 production and signaling in a murine model of bacterial infection. Specific Aim 2. Examine the role of Chi3l1 and IL13RD2 in the regulation of endosomal trafficking of TLR9 during bacterial infection in vitro and in a mouse model. Specific Aim 3. Determine which cells are critically required for Chi3l1 and IFN-1 production during infection, and determine the clinical significance of Chi3l1 and IFN-1 in bacterial infection. This project aims to understand the mechanisms of pathogen-related immunopathology during bacterial infection, including the mechanisms by which Chi3l1 modulates the IFN-1 response to control immunopathology. We will also explore the role of Chi3l1 in endosomal trafficking of TLRs during infection and assess the use of Chi3l1 as a prognostic biomarker in infected patients. The data generated from this application are expected to provide novel insights that promote the development of new therapies for bacterial infection.

描述（由申请方提供）：细菌性肺炎和败血症是重症监护室中主要的可预防死亡原因，肺炎链球菌（Sp）是主要病因。目前的治疗主要集中在使用抗生素，并导致迅速出现耐药性和高毒力菌株。成功的病原体-宿主相互作用的一个基本方面是在成功清除病原体的同时保持有害的、组织损伤的炎症免疫应答的能力。在细菌感染中观察到的夸大的发病率和死亡率可能是炎症失调的结果。目前没有可行的治疗方式来增强宿主防御，同时减少不必要的炎症。此外，人们对信号级联如何收敛以控制宿主防御，同时最大限度地减少炎症组织损伤还知之甚少。考虑到这一点，我们已经确定了几丁质酶3-样1（Chi 3l 1），一个原型几丁质酶样蛋白的18-糖基水解酶家族，在这一过程中是重要的。我们发现Chi 3l 1 是一种有效的先天免疫调节剂，在患有以炎症和组织修复为特征的疾病的患者中升高。Chi 3l 1，沿着其新发现的受体IL 13 RD 2，在Sp感染期间被诱导，并且在抗菌反应中是关键的。Chi 3l 1-IL 13 RD 2轴作为控制细菌感染期间潜在有害的先天免疫激活的治疗靶标是重要的。我们的数据表明，Chi 3l 1-IL 13 RD 2相互作用严重抑制潜在有害的I型干扰素（IFN-1）在感染过程中的反应。Chi 3l 1或IL 13 RD 2的缺乏导致感染期间IFN-1升高，这与内体Toll样受体9（TLR 9）和干扰素调节因子7（IRF 7）的共定位增加有关。我们的总体假设是Chi 3l 1-IL 13 RD 2通过调节IFN-1通路来抑制过度炎症和组织损伤。我们将测试这个假设与以下具体目标：具体目标1.描述Chi 3l 1及其受体IL 13 RD 2在细菌感染的小鼠模型中调节IFN-1产生和信号传导的机制。具体目标2。检查Chi 3l 1和IL 13 RD 2在体外细菌感染和小鼠模型中调节TLR 9内体运输的作用。具体目标3。确定感染期间Chi 3l 1和IFN-1产生所需的细胞，并确定Chi 3l 1和IFN-1在细菌感染中的临床意义。该项目旨在了解细菌感染过程中病原体相关的免疫病理学机制，包括Chi 3l 1调节IFN-1应答以控制免疫病理学的机制。我们还将探讨Chi 3l 1在感染过程中TLR内体转运中的作用，并评估Chi 3l 1作为感染患者预后生物标志物的用途。该应用程序产生的数据有望提供新的见解，促进细菌感染新疗法的开发。