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：
10206840
负责人：
John F Alcorn
金额：
$ 50.64万
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 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10206840
关键词：
Address Age Animal Model Anti-Bacterial Agents Antibiotic Resistance Antibiotics Antiviral Agents Antiviral Therapy Area Attenuated Bacterial Infections Bacterial Pneumonia Binding Biological Assay Bone Marrow C Type Lectin Receptors CD209 gene Cartoons Cause of Death Cells Cessation of life Child Childhood Clinical Complex Coupled Data Disease Outbreaks Disease model Epithelial Cells Etiology Flow Cytometry Funding Goals Hematopoietic Host Defense Human Immune response Immunity Immunomodulators Impairment In Vitro Individual Influenza Influenza A virus Interferons Interleukin-1 beta Knockout Mice Laboratories Link LoxP-flanked allele Lung Mediating Modeling Molecular Morbidity - disease rate Mus Neutrophil Infiltration Orthologous Gene Pathway interactions Patient Care Patient-Focused Outcomes Patients Pattern recognition receptor Phagocytes Phagocytosis Phagocytosis Inhibition Pneumonia Population Pre-Clinical Model Predisposition Prevalence Publishing Regulation Risk Factors Role Seminal Signal Transduction Staphylococcus aureus Streptococcus pneumoniae T-Lymphocyte Therapeutic United States Vaccines Viral Virus Virus Diseases Work cell type comorbidity cytokine flu global health immune activation immune clearance immune function improved in vivo influenza infection influenza pneumonia influenzavirus interleukin-23 lung injury monocyte mortality mouse model new therapeutic target novel pandemic disease pathogen polarized cell pre-clinical receptor receptor expression superinfection uptake vaccine access

项目摘要

SUMMARY Pneumonia, caused by bacterial and/or viral etiology, is the leading cause of death in children worldwide. Preceding viral illness, linked to influenza infection, is a primary risk factor associated with secondary bacterial pneumonia. Influenza infection is an annual, seasonal cause of morbidity and mortality throughout the world. Severe influenza pneumonia is often exacerbated by bacterial infection resulting in poor patient outcomes even in previously healthy individuals. Further, secondary bacterial pneumonia with Staphylococcus aureus is increasing in prevalence and is now more common than Streptococcus pneumoniae, the previously predominant pathogen. The lack of effective anti-viral therapeutics, immunomodulatory drugs, and increasing antibiotic resistance, coupled with poor vaccine coverage and efficacy, results in a dire need for novel therapeutic target identification. The focus of this application is upon understanding the influenza-induced mechanisms of susceptibility to bacterial super-infection, the leading cause of death during seasonal and pandemic outbreaks. During the previous funding periods, our laboratory has identified suppression of bacterial-induced Type 17 immune responses by preceding influenza as a critical susceptibility mechanism. We have published extensively in this area, elucidating aberrant host defense pathways in this context. In this application, we will build upon our ongoing work with two highly novel Aims derived from the original focus. We now provide preliminary data implicating a detrimental role for type III interferon (IFNλ) in super-infection through inhibiting monocyte function and pattern recognition receptor expression. These data support the hypothesis that influenza induced IFNλ directly inhibits monocyte antibacterial function via suppression of SIGNR3/4, which is required for subsequent activation of Type 17 immunity and S. aureus clearance during super-infection. In Aim 1, we will determine the mechanism by which IFNλ inhibits monocyte function during influenza, S. aureus super-infection. In Aim 2, we will define the role of SIGNR3/4 in host defense against S. aureus in the lung. The proposed studies will further our understanding of how influenza impairs subsequent immunity against S. aureus (Aim 1) and how the immune response to influenza attenuate S. aureus clearance in the lung (Aim 2). Our overriding goal is to understand the critical mechanism(s) of susceptibility to influenza, S. aureus super-infection and identify novel treatment targets in a pre-clinical model of disease.

概括由细菌和/或病毒病因引起的肺炎是全球儿童死亡的主要原因。与影响力感染有关的病毒疾病是与继发细菌相关的主要危险因素肺炎。流感感染是全世界发病率和死亡率的年度季节性原因。严重的影响力肺炎通常会因细菌感染而加剧，甚至导致患者预后不良在以前健康的个体中。此外，带有金黄色葡萄球菌的继发细菌性肺炎是患病率的增加，现在比肺炎链球菌更常见主要病原体。缺乏有效的抗病毒疗法，免疫调节药物和增加抗生素耐药性，再加上疫苗覆盖不良和效率，导致对新颖的需求治疗靶标识别。该应用的重点是了解影响力引起的影响易感性超级感染的机制，是季节性死亡的主要原因和大流行爆发。在前前的资金期间，我们的实验室已经确定了对细菌诱导的17型免疫反应先于影响力作为关键的敏感性机制。我们已经在这一领域广泛发表，在这种情况下阐明了异常的宿主防御途径。在这个应用程序，我们将以两个高新颖的目标从原始焦点衍生出来的两个高新颖的目标来建立我们的工作。我们现在提供初步数据，牵涉到超级感染中III型干扰素（IFNλ）的有害作用通过抑制单核细胞功能和模式识别受体表达。这些数据支持影响IFNλ直接抑制单核细胞抗菌功能的假设通过抑制 SIGNR3/4，这是随后激活17型免疫和金黄色葡萄球菌间隙所必需的超级感染。在AIM 1中，我们将确定IFNλ抑制单核细胞功能的机制流感，S。金黄色的超级感染。在AIM 2中，我们将定义Signr3/4在对抗S的宿主防御中的作用。肺中的金黄色。拟议的研究将进一步理解影响力如何损害随后的对金黄色葡萄球菌的免疫力（AIM 1）以及对影响衰减金黄色葡萄球菌清除的免疫反应如何在肺中（目标2）。我们的压倒性目标是了解影响力易感性的关键机制，金黄色葡萄球菌超级感染并确定疾病前临床模型中的新型治疗靶标。