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

• 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
• 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

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.

总结 由细菌和/或病毒病因引起的肺炎是全世界儿童死亡的主要原因。 先前的病毒性疾病，与流感感染有关，是继发性细菌感染的主要危险因素。 肺炎流感感染是全世界每年一次、季节性发病和死亡的原因。 严重的流感肺炎通常会因细菌感染而加重，导致患者预后不良， 在以前健康的人。此外，继发性细菌性肺炎与金黄色葡萄球菌， 流行率增加，现在比肺炎链球菌更常见，以前 优势病原体缺乏有效的抗病毒治疗，免疫调节药物， 抗生素耐药性，加上疫苗覆盖率和功效较差，导致对新型疫苗的迫切需求 治疗靶点识别本申请的重点是了解流感引起的 对细菌双重感染的易感性机制，这是季节性和季节性期间死亡的主要原因， 大流行的爆发。在过去的资助期间，我们的实验室已经确定了抑制 细菌诱导的17型免疫反应，作为一个关键的易感性机制。 我们已经在这一领域发表了大量文章，阐明了在这种情况下异常的宿主防御途径。在这 应用程序，我们将建立在我们正在进行的工作与两个高度新颖的目标来自原来的重点。我们 现在提供的初步数据暗示了III型干扰素（IFNλ）在双重感染中的有害作用 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 假设流感诱导的IFNλ通过抑制 SIGNR 3/4，这是随后激活17型免疫和S.金黄色葡萄球菌清除率 超级感染在目的1中，我们将确定IFNλ在单核细胞增殖过程中抑制单核细胞功能的机制。 流感，S.金黄色葡萄球菌双重感染。在目的2中，我们将定义SIGNR 3/4在宿主防御S中的作用。 肺部有金黄色葡萄球菌拟议的研究将进一步了解流感如何损害随后的 抗S.金黄色葡萄球菌（目的1）和如何免疫应答流感减毒S。金黄色葡萄球菌清除率 在肺中（目标2）。我们的首要目标是了解流感易感性的关键机制， S.金黄色葡萄球菌的超感染，并在疾病的临床前模型中确定新的治疗靶点。