Neutrophil Function in Bacterial Pneumonia

细菌性肺炎中的中性粒细胞功能

• 批准号: 8839361
• 负责人: Samithamby Jeyaseelan
• 金额: $ 38.16万
• 依托单位: LOUISIANA STATE UNIV A&M COL BATON ROUGE
• 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/8839361
• 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; Caspase; Caspase-1; 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-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; 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

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-1ß as a major regulator of immunity to Klebsiella pneumonia. We show that: (1) human lungs with bacterial pneumonia display higher IL-1ß expression by neutrophils; (2) human and mouse neutrophils show elevated IL-1ß production following K. pneumoniae infection; (3) both caspase-1 and -11 activation by K. pneumoniae are essential for IL-1ß production by neutrophils; (4) human and mouse neutrophils produce IL-17A during bacterial infection in an IL-1ß dependent manner; (5) IL-1ß but not IL-1α or IL-18 is important for survival in response to K. pneumoniae infection; and (6) neutrophil depletion greatly reduces IL-1ß but not IL-18 or IL-1α in the lungs after K. pneumoniae challenge. These observations have led us to hypothesize that neutrophil-derived IL-1ß is a key defense mechanism that regulates immunity via modulating IL-17 production. Little is known regarding the role of neutrophil- derived IL-1ß in bacterial pneumonia. The Aims are: (1) Delineate the in vivo mechanisms that modulate IL-1ß production and neutrophil function during Klebsiella pneumonia; (2) Determine the effects of neutrophil-derived IL-1ß on IL-17A and IL-17F responses to bacterial pneumonia; and (3) Determine if manipulation of neutrophil-derived IL-1ß expression 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（由申请方提供）：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，肺炎占急性肺损伤/急性呼吸窘迫综合征（ALI/ARDS）患者的最大数量。从LRT中成功清除病原体取决于有效的先天免疫应答。了解LRT中的先天防御机制对于开发新的免疫治疗剂或疫苗以减少这种疾病负担至关重要。触发先天性免疫应答的信号传导级联由促进病原体清除的促炎应答与控制过度全身性炎症的抵消抗炎应答之间的微妙平衡组成。人们对这些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性组织损伤还知之甚少。作为阐明基本宿主防御机制的模型，我们重点研究了主要病原体肺炎克雷伯氏菌，因为这种细胞外革兰氏阴性细菌会导致严重肺炎;并且已经出现了多种耐药和高毒力变体。我们新的初步数据支持嗜中性粒细胞衍生的IL-1 β作为克雷伯氏肺炎免疫的主要调节剂的新作用。我们证明：（1）人肺炎患者肺组织中性粒细胞IL-1 β表达增高;（2）人和小鼠嗜中性粒细胞在肺炎克雷伯氏菌感染后IL-1 β表达增高。pneumoniae感染;（3）K.肺炎克雷伯氏菌感染后，人和小鼠的中性粒细胞以IL-1 β依赖的方式产生IL-17 A，IL-1 β而不是IL-1α或IL-18对机体的存活起重要作用。肺炎克雷伯氏菌感染后，中性粒细胞减少可显著降低肺内IL-1 α，但对IL-18和IL-1α无影响。肺炎攻毒。这些观察结果使我们假设嗜中性粒细胞衍生的IL-17是通过调节IL-17产生来调节免疫的关键防御机制。关于中性粒细胞来源的IL-1 β在细菌性肺炎中的作用知之甚少。目标是：（1）描述在肺炎克雷伯氏菌过程中调节IL-1 β产生和中性粒细胞功能的体内机制;（2）确定嗜中性粒细胞来源的IL-1 β对细菌性肺炎的IL-17 A和IL-17 F应答的影响;（3）确定在肺炎克雷伯氏菌过程中，操纵嗜中性粒细胞来源的IL-1 β表达是否可以改变宿主的抵抗力。将采用体内和体外系统的独特组合，包括KO小鼠、慢病毒转导和过继转移策略来解决这些目标。这是一个概念上，技术上和预防上的创新建议，将在研究人员和临床医生对细菌性肺炎的思考方式中建立一个范式转变，并最终导致细菌性肺炎治疗的改进治疗和预防策略。