Neutrophil Function in Bacterial Pneumonia

细菌性肺炎中的中性粒细胞功能

基本信息

批准号：
8969664
负责人：
Samithamby Jeyaseelan
金额：
$ 36.96万
依托单位：
LOUISIANA STATE UNIV A&M COL BATON ROUGE
依托单位国家：
美国
项目类别：
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/8969664
关键词：
Accounting Acute Acute Lung Injury Address Adoptive Transfer Adult Adult Respiratory Distress Syndrome Agonist Anti-Inflammatory Agents Anti-inflammatory Antibiotic Therapy Antimicrobial Resistance Bacteria Bacterial Infections Bacterial Pneumonia Biology Bone Marrow CASP1 gene Caspase Cause of Death Cells Chemotaxis Child Chronic Obstructive Airway Disease Data Defense Mechanisms Development Disease Drug resistance Equilibrium Event Foundations Frequencies Goals Gram-Negative Bacteria Health Host Defense Host Defense Mechanism Host resistance Human Immune Immune response Immune system Immunity Immunotherapeutic agent Impairment In Vitro Individual Infection Inflammation Inflammatory Inflammatory Response Injury Interleukin-1 Interleukin-1 alpha Interleukin-17 Interleukin-18 Investigation Klebsiella pneumonia bacterium Knockout Mice Knowledge Lead Lower Respiratory Tract Infection Lower respiratory tract structure Lung Mediating Modeling Molecular Molecular Models Morbidity - disease rate Multi-Drug Resistance Mus N-terminal Natural Immunity Neutropenia Organ Patients Peptide Hydrolases Phagocytosis Pneumonia Population Prevention strategy Production Publishing Recurrence Reporting Research Research Personnel Role STAT3 gene Sepsis Severities Signal Transduction Staging System T-Lymphocyte Therapeutic Thinking Tissues Vaccines Variant Work burden of illness cytokine design extracellular immune function improved in vivo innovation killings migration molecular modeling mortality neutrophil novel overexpression pathogen response transcription factor treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Acute lower respiratory tract (LRT) infections are a leading cause of global mortality and morbidity. Currently, pneumonia accounts for the largest number of Acute Lung Injury/Acute Respiratory Distress Syndrome (ALI/ARDS) patients. Successful clearance of pathogens from the LRT is dependent on effective innate immune responses. Understanding the innate defense mechanisms in the LRT is critical for the development of novel immunotherapeutics or vaccines to reduce this burden of disease. The signaling cascades triggering innate immune responses consist of a delicate balance between pro- inflammatory responses that facilitate pathogen clearance, and counteracting anti-inflammatory responses that control excessive systemic inflammation. It is poorly understood how these signaling cascades converge to control host defense while minimizing inflammatory tissue injury. As a model to elucidate the basic host defense mechanisms, we have focused on a primary pathogen, Klebsiella pneumoniae because this extracellular Gram-negative bacterium causes severe pneumonia; and multiple drug-resistant and hypervirulent variants have emerged. Our new preliminary data support a novel role for neutrophil-derived IL-1�s a major regulator of immunity to Klebsiella pneumonia. We show that: (1) human lungs with bacterial pneumonia display higher IL-1�xpression by neutrophils; (2) human and mouse neutrophils show elevated IL-1�roduction following K. pneumoniae infection; (3) both caspase-1 and -11 activation by K. pneumoniae are essential for IL-1�roduction by neutrophils; (4) human and mouse neutrophils produce IL-17A during bacterial infection in an IL-1�ependent manner; (5) IL-1�ut not IL-1�r IL-18 is important for survival in response to K. pneumoniae infection; and (6) neutrophil depletion greatly reduces IL-1�ut not IL-18 or IL-1�n the lungs after K. pneumoniae challenge. These observations have led us to hypothesize that neutrophil-derived IL-1�s a key defense mechanism that regulates immunity via modulating IL-17 production. Little is known regarding the role of neutrophil- derived IL-1�n bacterial pneumonia. The Aims are: (1) Delineate the in vivo mechanisms that modulate IL-1�roduction and neutrophil function during Klebsiella pneumonia; (2) Determine the effects of neutrophil-derived IL-1�n IL-17A and IL-17F responses to bacterial pneumonia; and (3) Determine if manipulation of neutrophil-derived IL-1�xpression can alter host resistance during Klebsiella pneumonia. A unique combination of in vivo and in vitro systems, including KO mice, lentiviral transduction and adoptive transfer strategies will be employed to address these aims. This is a conceptually, technically and translationally innovative proposal that will establish a paradigm shift in the way researchers and clinicians think about bacterial pneumonia and ultimately lead to improved therapeutic and prevention strategies of the treatment of bacterial pneumonia.

描述（由申请人提供）：急性下呼吸道（LRT）感染是全球死亡率和发病率的主要原因，目前，肺炎是导致急性肺损伤/急性呼吸窘迫综合征（ALI/ARDS）患者数量最多的原因。 LRT 中病原体的清除取决于有效的先天免疫反应，了解 LRT 中的先天防御机制对于开发新型免疫疗法或疫苗来减少这种情况至关重要。触发先天免疫反应的信号级联由促进病原体清除的促炎反应和控制过度全身炎症的抗炎反应之间的微妙平衡组成，但人们对这些信号级联如何汇聚以控制宿主知之甚少。作为阐明基本宿主防御机制的模型，我们重点关注一种主要病原体——肺炎克雷伯菌，因为这种细胞外革兰氏阴性细菌会引起严重的肺炎和多发性肺炎。我们的新初步数据支持中性粒细胞来源的 IL-1 是克雷伯氏菌肺炎免疫的主要调节剂的新作用，我们表明：（1）患有细菌性肺炎的人类肺部表现出较高的 IL-1。中性粒细胞的表达；(2) 肺炎克雷伯菌感染后，人类和小鼠中性粒细胞的 IL-1 表达升高；(3) 肺炎克雷伯菌感染后，caspase-1 和 -11 均被激活。肺炎链球菌对于中性粒细胞产生 IL-1 至关重要；(4) 人和小鼠中性粒细胞在细菌感染期间以 IL-1 依赖性方式产生 IL-17A；(5) IL-1，而不是 IL-1。 -18 对于肺炎克雷伯菌感染后的生存很重要；(6) 肺炎克雷伯菌感染后，中性粒细胞耗竭会大大降低肺部的 IL-1，而不是 IL-18 或 IL-1。这些观察结果使我们怀疑中性粒细胞衍生的 IL-1 是一种通过调节 IL-17 产生来调节免疫的关键防御机制，而关于中性粒细胞衍生的 IL-1 在细菌性肺炎中的作用知之甚少。是：(1) 描述克雷伯氏菌肺炎期间调节 IL-1 产生和中性粒细胞功能的体内机制；(2) 确定中性粒细胞衍生的 IL-1 的作用； IL-17A 和 IL-17F 对细菌性肺炎的反应；以及（3）确定中性粒细胞来源的 IL-1 表达的操作是否可以改变克雷伯氏菌肺炎期间宿主的抵抗力，包括 KO 小鼠、慢病毒。将采用转导和收养转移策略来实现这些目标，这是一个概念上、技术上和转化上的创新提案，将在方式上建立范式转变。研究人员和信徒对细菌性肺炎的思考最终导致细菌性肺炎治疗和预防策略的改进。