Effect of Influenza Infection on Alveolar Macrophage Function

描述（由申请人提供）：本拟议项目的总体目标是了解流感感染后肺炎链球菌易感性增强的机制。尽管这是一个公认的临床问题，在人类流感大流行（包括1918年大流行）期间，即使不是大多数人死亡，也会导致许多人死亡，但我们仍然对这种微生物协同作用的原因知之甚少。利用PI实验室建立的流感和肺炎球菌小鼠感染模型，我们现在已经表明，在流感感染的恢复期，当IFN-3+ T细胞迁移到肺中时，肺泡巨噬细胞对MARCO清道夫受体有显著的抑制作用，未调理的肺炎球菌的清除受到抑制，动物死亡率增加。这些抑制作用在IFN-3-/-小鼠中不发生，并且可以通过在病毒感染后接种抗IFN-3 mAb来预防。本提案中的研究旨在充分了解流感病毒感染诱导的吞噬细胞功能变化以及负责抑制肺部细菌清除的机制。该假说是，针对肺中细胞内病原体（流感病毒）的适应性免疫应答的诱导导致先天性肺泡巨噬细胞介导的针对细胞外病原体的保护的显著损害（S.肺炎）。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道夫受体和TLR功能是否发生对先天免疫有害的变化。还将评估对其他吞噬细胞群的可能影响。负责IFN-3在肺中的活性的机制将被确定，包括对肺泡巨噬细胞的直接影响和T细胞和上皮细胞的可能的中介作用，以及TGF-2的潜在作用。将使用过继细胞转移和缺乏特定细胞亚群的小鼠研究流感感染导致肺泡巨噬细胞抑制的效应细胞。最后，我们将详细研究粘膜疫苗接种策略的潜力，包括使用经批准的冷适应性FluMist（R）疫苗，以模拟病毒感染并诱导对呼吸道细菌感染的易感性增强。我们的最终目标是了解负责病毒-细菌协同作用的免疫学过程，并利用所获得的信息，以设计新的治疗方法来预防人类对这些病原体的易感性增强。 公共卫生相关性：本研究的重点是了解继发性细菌感染的机制，这些感染通常发生在流感病毒感染之后，并且是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，了解微生物在肺道的相互作用，从而提供重要的见解，为人类使用的有效治疗的发展。

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.