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Targeting macrophage Bcl6 to enhance innate resistance to influenza

靶向巨噬细胞 Bcl6 增强对流感的先天抵抗力

基本信息

批准号：
8947649
负责人：
Jie Sun
金额：
$ 23.4万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8947649
关键词：
Alveolar Macrophages Antibodies Antiviral Agents Attenuated BCL6 gene Binding Data Development Disease Disease Outbreaks Economics Epithelial Cells Exhibits Functional disorder Future Genes Goals Host resistance Human Immune Immune response Immunity Infection Influenza Influenza A Virus, H5N1 Subtype Influenza A Virus, H7N9 Subtype Influenza prevention Integration Host Factors Interferons Knockout Mice Lead Light Lung Mediating Methods Modality Morbidity - disease rate Myeloid Cells Natural Immunity Pathogenesis Pattern recognition receptor Peptide Hydrolases Pharmaceutical Preparations Predisposition Preventive Production Public Health Reporting Resistance Resistance development Signal Transduction Surface Antigens Testing Therapeutic Time Tretinoin United States Vaccination Viral Virion Virus Virus Diseases Virus Replication cell type cytokine global health in vivo influenza virus strain influenzavirus inhibitor/antagonist interest killings macrophage mortality novel novel therapeutics pandemic influenza public health relevance seasonal influenza social transmission process

项目摘要

DESCRIPTION (provided by applicant): In this application, we will test the hypothesis that the Bcl6 gene, specifically in macrophages, inhibits host antiviral immunity and promotes host susceptibility to influenza virus infection. We will also explore whether the inhibition of Bcl6 function will enhance host anti-viral immunity to influenza and ameliorate severe host diseases during influenza virus infection. Two specific aims have been proposed. Specific Aim 1: To elucidate the underlying mechanisms by which Bcl6 deletion in macrophages attenuates influenza virus infection. Specific Aim 2: To determine if the inhibition of Bcl6 expression and/or function promotes macrophage IFN production and increase host resistance to influenza virus infection. The successful completion of this application will not only shed light on novel mechanisms of influenza pathogenesis and immune protection, but also open the door to developing novel therapeutic modalities against influenza infection in the near future. Relevance statement Seasonal influenza kills ~500,000 people globally and up to 50,000 people in the United States each year. In addition to seasonal outbreaks, pandemic influenza viruses occasionally emerge when humans are introduced to a virus to which they are immunologically naïve. Over the last decade, highly pathogenic avian influenza viruses (H5N1, H7N9) have emerged and recent data have highlighted the serious threat of another potential devastating influenza pandemic involving highly pathogenic virus strains. Current strategies for influenza prevention and treatment include yearly vaccination and anti-viral drugs. However, frequent changes in the surface antigens of influenza virus allow influenza viruses to escape antibody-mediated immune protection following vaccination and many circulating influenza virus strains have developed resistance to the current antiviral drugs. Thus, there is urgent need to understand the pathophysiology and the protective immune responses to influenza virus infection for the development of future preventive and therapeutic approaches. We believe that the novel method we employ here may provide alternative therapeutic modalities to those influenza virus strains that have already developed resistance to current anti-viral drugs.

描述（由申请人提供）：在本申请中，我们将检验以下假设：Bcl 6基因（特别是巨噬细胞中的Bcl 6基因）抑制宿主抗病毒免疫并促进宿主对流感病毒感染的易感性。我们还将探讨抑制Bcl 6功能是否会增强宿主对流感的抗病毒免疫力，并改善流感病毒感染期间严重的宿主疾病。提出了两个具体目标。具体目标1：阐明巨噬细胞中Bcl 6缺失减弱流感病毒感染的潜在机制。具体目的2：确定是否抑制Bcl 6表达和/或Bcl 8蛋白表达。功能促进巨噬细胞IFN的产生并增加宿主对流感病毒感染的抵抗力。该申请的成功完成不仅将揭示流感发病机制和免疫保护的新机制，而且还为在不久的将来开发针对流感感染的新治疗方法打开了大门。季节性流感每年在全球造成约50万人死亡，在美国造成多达5万人死亡。除了季节性爆发外，大流行性流感病毒偶尔也会在人类接触到一种免疫学上尚不熟悉的病毒时出现。在过去十年中，出现了高致病性禽流感病毒（H5 N1，H7N9），最近的数据突出了另一种涉及高致病性病毒株的潜在破坏性流感大流行的严重威胁。目前的流感预防和治疗策略包括每年接种疫苗和抗病毒药物。然而，流感病毒表面抗原的频繁变化使得流感病毒在接种疫苗后逃避抗体介导的免疫保护，并且许多流行的流感病毒株已经对当前的抗病毒药物产生了耐药性。因此，迫切需要了解流感病毒感染的病理生理学和保护性免疫反应，以发展未来的预防和治疗方法。我们相信，我们在这里采用的新方法可能会提供替代的治疗方式，这些流感病毒株已经发展到目前的抗病毒药物的耐药性。