Effect of Influenza Infection on Alveolar Macrophage Function

描述(由申请人提供)：这项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加的机制。尽管这是一个公认的临床问题，在人类流感大流行期间，包括1918年的大流行期间，即使不是导致大多数人死亡，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，我们现在已经证明，在流感感染的恢复期，当干扰素-3T细胞迁移到肺部时，肺泡巨噬细胞显著抑制Marco清道夫受体，抑制未调理肺炎球菌的清除，并增加动物死亡率。这些抑制作用不会发生在干扰素-3-/-小鼠身上，并且可以通过病毒感染后接种抗-干扰素-3单抗来预防。这项建议中的研究现在旨在充分了解流感病毒感染诱导的吞噬细胞的功能变化，以及抑制肺部细菌清除的机制。该假说认为，诱导对肺部细胞内病原体(流感病毒)的适应性免疫反应会导致先天肺泡巨噬细胞介导的对细胞外病原体(肺炎链球菌)的保护作用显著减弱。为了测试这些概念，将检测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功能是否发生了不利于天然免疫的变化。还将评估对其他吞噬细胞群的可能影响。将确定导致肺内干扰素-3活性的机制，包括对肺泡巨噬细胞的直接影响，对T细胞和上皮细胞的可能中介作用，以及转化生长因子-2的潜在作用。负责流感感染抑制肺泡巨噬细胞的效应细胞(S)将通过过继细胞转移和缺乏特定细胞亚群的小鼠进行研究。最后，我们将详细研究粘膜疫苗接种策略的可能性，包括使用经批准的冷适应FluMist(R)疫苗，以模拟病毒感染并增加对呼吸道细菌感染的易感性。我们的最终目标是了解导致病毒-细菌协同作用的免疫学过程，并利用所获得的信息来设计新的治疗方法，以防止人类对这些病原体的易感性增加。 公共卫生相关性：这项研究的重点是了解继发性细菌感染的机制，这些继发性细菌感染通常伴随着流感病毒感染，是人类发病率和死亡率的重要原因。这项研究的结果将为理解肺部微生物的相互作用提供一个全面的模型，从而为开发有效的治疗方法提供重要的见解。

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.