Neutrophil Function in 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，在急性肺损伤/急性呼吸窘迫综合征（ALI/ARDS）患者中，肺炎占比最大。成功清除LRT中的病原体依赖于有效的先天免疫反应。了解LRT的先天防御机制对于开发新型免疫疗法或疫苗以减轻这种疾病负担至关重要。触发先天免疫反应的信号级联包括促进病原体清除的促炎反应和抑制控制过度全身炎症的抗炎反应之间的微妙平衡。目前尚不清楚这些信号级联如何汇聚控制宿主防御，同时最大限度地减少炎症组织损伤。作为阐明宿主基本防御机制的模型，我们将重点放在了一种主要病原体肺炎克雷伯菌上，因为这种细胞外革兰氏阴性菌会导致严重的肺炎；并且出现了多种耐药和高致病性变种。我们新的初步数据支持中性粒细胞来源的IL-1的新作用，IL-1是克雷伯氏菌肺炎免疫的主要调节因子。结果表明：(1)细菌性肺炎患者肺中中性粒细胞表达IL-1 α较高；(2)肺炎克雷伯菌感染后，人和小鼠中性粒细胞IL-1 -的产生升高；(3)肺炎克雷伯菌激活caspase-1和-11是中性粒细胞产生IL-1的必要条件；(4)人和小鼠中性粒细胞在细菌感染过程中以依赖于IL-1的方式产生IL-17A；(5) IL-1 -而非IL-1 -或IL-18对肺炎克雷伯菌感染患者的生存有重要影响；(6)中性粒细胞耗竭可显著降低肺炎克雷伯菌攻击后肺中的IL-1 -，而非IL-18或IL-1 -。这些观察结果使我们假设中性粒细胞衍生的IL-1是通过调节IL-17的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在细菌性肺炎中的作用知之甚少。目的是：(1)阐明肺炎克雷伯菌体内调节IL-1生成和中性粒细胞功能的机制；(2)确定中性粒细胞源性IL-1、IL-17A和IL-17F对细菌性肺炎的影响；(3)确定操纵中性粒细胞来源的IL-1表达是否可以改变克雷伯菌肺炎期间宿主的耐药性。一个独特的体内和体外系统的组合，包括KO小鼠，慢病毒转导和过继转移策略将被用来解决这些目标。这是一个概念上、技术上和翻译上的创新建议，将建立一种范式转变的方式

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.