Influenza A Inhibits TH17 Host Defense Against Bacterial Pneumonia

甲型流感抑制 TH17 宿主对细菌性肺炎的防御

基本信息

批准号：
8399082
负责人：
John F Alcorn
金额：
$ 35.47万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-01-01 至 2016-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8399082
关键词：
Acute Lung Injury Address Bacteria Bacterial Infections Bacterial Pneumonia CD4 Positive T Lymphocytes Cells Cellular Immunity Cessation of life Coupled Cytokine Signaling Data Dendritic Cells Disease Outbreaks Down-Regulation Epithelial Epithelial Cells Escherichia coli Genes Goals Hospitals Host Defense Human Immune response Immunity In Vitro Incidence Infection Influenza Influenza A Virus, H1N1 Subtype Influenza A virus Interferon Suppression Interferon Type I Interferons Interleukin-17 Intervention Knockout Mice Laboratories Link Lung Mediating Methicillin Resistance Modeling Molecular Morbidity - disease rate Mus Neutrophil Infiltration Outcome Pathway interactions Patients Peptides Pneumonia Population Predisposition Production Resolution Risk Role STAT1 gene STAT2 gene Severities Source Staphylococcus aureus Streptococcus pneumoniae T-Lymphocyte United States Virulence Factors airway epithelium antimicrobial antimicrobial peptide cell mediated immune response cytokine extracellular immune activation improved interleukin-22 interleukin-23 killings mortality mouse model new therapeutic target novel therapeutics pandemic disease pathogen resistant strain secondary infection superinfection

项目摘要

DESCRIPTION (provided by applicant): Influenza A H1N1 represents a major cause of morbidity and mortality in the United States. In addition, Influenza A poses a significant risk of pandemic outbreak as evidenced in the past two years. A large proportion of severe cases of Influenza A pneumonia are associated with secondary bacterial infection, most commonly caused by Staphylococcus aureus or Streptococcus pneumoniae. Incidence and severity of S. aureus pneumonia is increasing worldwide due to the emergence of methicillin-resistant (MRSA) strains. For these reasons, understanding the molecular mechanisms that promote bacterial host defense in the lung is of critical importance. Little is known about the cell-mediated immune response to S. aureus infection. Using a mouse model of Influenza A infection (Influenza A PR/8/34) coupled with S. aureus challenge our group has found that Influenza A exacerbates secondary bacterial pneumonia. We have shown that the mechanism is likely mediated by type I Interferon suppression of IL-23 production and subsequent TH17 immune activation. In this proposal we will further investigate the Influenza A, S. aureus co-infection model in three specific aims. First, we will examine the role of type I interferon in mediating Influenza A exacerbation of secondary bacterial infection. Second, we will examine the mechanism by which IL-23 promotes immunity against S. aureus. Finally, we will investigate the mechanism by which the TH17 pathway promotes S. aureus killing via the airway epithelium. These studies will involve numerous TH17 pathway gene altered mouse studies and in vitro studies with both mouse and human airway epithelial cells. The goal of the study is to elucidate the molecular mechanisms involved in S. aureus host defense and to identify interventions that can restore TH17 immunity following Influenza A infection and improve the host response against secondary bacterial pneumonia. These data may be directly applicable to the hospital setting and may reveal novel therapeutic strategies that would decrease morbidity and mortality, and improve patient outcome.

描述（由申请人提供）：流感A H1N1代表了美国发病率和死亡率的主要原因。此外，在过去两年中，流感A构成了大流行爆发的重大风险。很大一部分严重的流感病例A肺炎与继发性细菌感染有关，最常见的是金黄色葡萄球菌或肺炎链球菌引起的。由于耐甲氧西林（MRSA）菌株的出现，全球金黄色葡萄球菌的发病率和严重程度正在增加。由于这些原因，了解促进肺部细菌宿主防御的分子机制至关重要。关于细胞介导的对金黄色葡萄球菌感染的免疫反应知之甚少。使用流感A感染的小鼠模型（流感A PR/8/34），再加上我们小组的金黄色葡萄球菌挑战，发现流感A A A型流感症状症状。我们已经表明，该机理可能是由I型干扰素抑制IL-23产生和随后的TH17免疫激活介导的。在此提案中，我们将进一步研究三个特定目标的Aureus S. Aureus共感染模型。首先，我们将研究I型干扰素在介导流感的次生细菌感染中的作用。其次，我们将研究IL-23促进对金黄色葡萄球菌的免疫力的机制。最后，我们将研究TH17途径通过气道上皮促进金黄色葡萄球菌杀死的机制。这些研究将涉及许多TH17途径基因改变小鼠研究和对小鼠和人类气道上皮细胞的体外研究。该研究的目的是阐明金黄色葡萄球菌宿主防御中涉及的分子机制，并确定可以在感染流感后可以恢复Th17免疫的干预措施，并改善针对次生细菌性肺炎的宿主反应。这些数据可能直接适用于医院环境，并可能揭示了新的治疗策略，这些策略将降低发病率和死亡率，并改善患者的预后。