Effect of Influenza Infection on Alveolar Macrophage Function

流感感染对肺泡巨噬细胞功能的影响

基本信息

批准号：
7590259
负责人：
DENNIS W METZGER
金额：
$ 39.25万
依托单位：
ALBANY MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-12 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7590259
关键词：
Adoptive Cell Transfers Alveolar Macrophages Anti-Bacterial Agents Antigens Bacteria Bacterial Infections Binding Bone Marrow CD8B1 gene Cells Cessation of life Clinical Data Development Disease Effectiveness Effector Cell Epithelial Cells Flow Cytometry Flushield Goals Human Immune Immune response Immunodeficient Mouse Impairment In Vitro Individual Infection Infectious Agent Influenza Interferons Laboratories Lung Mediating Modeling Morbidity - disease rate Mus Natural Immunity Nature Peritoneal Macrophages Phagocytes Phagocytosis Phase Phenotype Pneumococcal Infections Population Positioning Attribute Predisposition Prevention Procedures Process Property Recovery Relative (related person)Reporting Respiratory System Respiratory tract structure Reverse Transcriptase Polymerase Chain Reaction Role Secondary to Series Specificity Streptococcus pneumoniae T-Lymphocyte Testing The Sun Therapeutic Time Vaccines Viral Virus Virus Diseases animal mortality cytokine design extracellular in vivo influenzavirus insight interest macrophage macrophage scavenger receptors microbial microorganism interaction mortality mucosal vaccination neutralizing antibody neutrophil novel therapeutic intervention pandemic disease pandemic influenza pathogen prevent public health relevance receptor expression research study respiratory response scavenger receptor vaccination strategy virus infection mechanism

项目摘要

DESCRIPTION (provided by applicant): The overall objective of this proposed project is to understand the mechanisms responsible for enhanced susceptibility to Streptococcus pneumoniae that follows influenza infection. Despite being a recognized clinical problem that causes many, if not the majority of deaths during human influenza pandemics, including the 1918 pandemic, we still know only very little about the reasons for this microbial synergy. Taking advantage of influenza and pneumococcal mouse infection models that are established in the PI's laboratory, we have now shown that during the recovery phase of influenza infection, when IFN-3+ T cells migrate into the lung, there is significant inhibition of the MARCO scavenger receptor by alveolar macrophages, suppressed clearance of unopsonized pneumococci, and increased animal mortality. These inhibitory effects do not occur in IFN-3-/- mice and can be prevented by inoculation of anti-IFN-3 mAb following viral infection. Studies in this proposal are now designed to fully understand the functional changes in phagocytic cells that are induced by influenza virus infection and the mechanisms responsible for inhibition of pulmonary bacterial clearance. The hypothesis is that induction of an adaptive immune response against an intracellular pathogen in the lung (influenza virus) results in significant impairment of innate alveolar macrophage-mediated protection against extracellular pathogens (S. pneumoniae). To test these concepts, the functional properties of phagocytic cells derived from mice recovering from influenza infection will be examined with a focus on determining whether shifts in alveolar macrophage scavenger receptor and TLR function occur that are detrimental for innate immunity. Possible effects on other phagocytic cell populations will also be assessed. The mechanisms responsible for IFN-3 activity in the lung will be determined, including direct influences on alveolar macrophages and possible intermediary roles for T and epithelial cells, as well as a potential role for TGF-2. The effector cell(s) responsible for alveolar macrophage inhibition by influenza infection will be investigated using adoptive cell transfers and mice lacking specific cell subsets. Finally, we will examine in detail the potential for mucosal vaccination strategies, including use of the approved cold-adapted FluMist(R) vaccine, to mimic viral infection and induce enhanced susceptibility to respiratory bacterial infections. Our ultimate goal is to understand the immunological processes responsible for virus-bacteria synergy and to exploit the information obtained in order to design novel therapeutic approaches for prevention of enhanced susceptibility of humans to these pathogens. PUBLIC HEALTH RELEVANCE: This study focuses on understanding the mechanisms responsible for secondary bacterial infections that often follow influenza virus infection and which represent a significant cause of morbidity and mortality in humans. The results obtained from this study will provide a comprehensive model for understanding microbial interactions in the pulmonary tract and thus provide important insight into the development of effective therapeutics for human use.

描述（由申请人提供）：该拟议项目的总体目标是了解导致影响流感感染后肺炎链球菌易感性的机制。尽管是一个公认的临床问题，它导致许多人在人类流感大流行中（包括1918年大流行）中的大多数死亡，但我们仍然只对这种微生物协同作用的原因知之甚少。 Taking advantage of influenza and pneumococcal mouse infection models that are established in the PI's laboratory, we have now shown that during the recovery phase of influenza infection, when IFN-3+ T cells migrate into the lung, there is significant inhibition of the MARCO scavenger receptor by alveolar macrophages, suppressed clearance of unopsonized pneumococci, and increased animal mortality.这些抑制作用不会发生在IFN-3 - / - 小鼠中，可以通过在病毒感染后通过接种抗IFN-3 MAB来预防。现在，该提案中的研究旨在充分了解由流感病毒感染诱导的吞噬细胞的功能变化以及负责抑制肺细菌清除率的机制。假设是，针对肺（流感病毒）对细胞内病原体的适应性免疫反应的诱导导致先天肺泡巨噬细胞介导的针对细胞外病原体（肺炎链球菌）的保护严重损害。为了测试这些概念，将检查源自从流感感染中恢复的小鼠的吞噬细胞的功能特性，重点是确定肺泡巨噬细胞清除剂受体的转移和TLR功能是否发生对先天免疫力有害。还将评估对其他吞噬细胞种群的可能影响。将确定负责IFN-3活性的机制，包括对T和上皮细胞的肺泡巨噬细胞的直接影响以及可能的中介作用，以及TGF-2的潜在作用。将使用缺乏特定细胞亚群的养细胞转移和小鼠研究，对流感感染抑制肺泡巨噬细胞的效应细胞将进行研究。最后，我们将详细研究粘膜疫苗接种策略的潜力，包括使用经认可的冷Flumist（R）疫苗来模仿病毒感染，并引起对呼吸细菌感染的敏感性增强。我们的最终目标是了解负责病毒 - 细菌协同作用的免疫过程，并利用获得的信息，以设计新型的治疗方法，以预防增强人类对这些病原体的敏感性。公共卫生相关性：本研究的重点是理解负责次要细菌感染的机制，这些机制通常遵循流感病毒感染，这代表了人类发病率和死亡率的重要原因。从这项研究中获得的结果将提供一个全面的模型，以了解肺部的微生物相互作用，从而为人类使用的有效治疗剂的开发提供了重要的见解。