Aging and Innate Immune Mechanisms in Pulmonary Infection

 描述（申请人提供）：老年人流感病毒性肺部感染和继发性细菌性肺炎的发病率和死亡率高于年轻人。然而，衰老损害宿主对呼吸道感染的防御的机制还不清楚。最近的人类遗传学研究表明，高表达的巨噬细胞移动抑制因子（MIF）等位基因赋予50%的生存受益于社区获得性肺炎的老年人。为了支持这一点，我们的初步数据表明，衰老与小鼠衰老肺内MIF的减少有关。此外，我们发现，在肺部，衰老和MIF缺乏症有几个共同的特点：增加衰老前肺部感染，增加肺损伤，并削弱流感病毒肺部感染后的病毒清除。重要的是，MIF缺乏也会影响流感病毒感染后的结果，随后是S。肺炎细菌感染。在这里，我们将通过研究两种临床相关的呼吸模型感染的遗传定义的小鼠来研究MIF在老化肺的感染加重期间的作用机制：原发性流感病毒和流感病毒感染后S。肺炎细菌感染。目的1将研究衰老和MIF缺乏损害流感病毒清除并增加肺损伤的机制，重点是I型干扰素的产生，这是一种对宿主防御病毒感染至关重要的炎症介质。目的2探讨MIF在老年继发性细菌感染后宿主防御中的作用。这两个目标都将考验 通过使用新的MIF转基因小鼠和新的药理学MIF调节剂。因此，这项提案将产生关于衰老的肺如何对呼吸道病原体做出反应的新信息，这可以为改善死于呼吸道感染的老年人的治疗提供新信息。

 DESCRIPTION (provided by applicant): Older people suffer from a higher morbidity and mortality from influenza viral lung infections and secondary bacterial pneumonia than younger people. Yet the mechanisms by which aging impairs host defense to respiratory infections are not well understood. Recent human genetic studies have shown that high expression of macrophage migration inhibitory factor (MIF) alleles confer a 50% survival benefit in older individuals with community-acquired pneumonia. In support of this, our preliminary data indicate that aging is associated with reduced MIF within the aging lung in mice. Furthermore, we show that in the lungs, aging and MIF deficiency share several features: increased senescence prior to lung infection, and increased lung damage, and impaired viral clearance after influenza viral lung infection. Importantly, MIF deficiency also worsens outcomes after influenza viral infection followed by S. pneumonia bacterial infection. Here, we will investigate the mechanisms underlying MIF's effects during infectious exacerbations of the aging lung by studying genetically-defined mice infected with two clinically-relevant respiratory models: primary influenza virus, and influenza viral infection followed by S. pneumonia bacterial infection. Aim 1 will investigate mechanisms by which aging and MIF deficiency impair clearance of influenza virus with increased lung damage, with a focus on type I interferon production, an inflammatory mediator that is critical to host defense against viral infection. Aim 2 will investigate the role f MIF in host defense after secondary bacterial infection with aging. Both Aims will test the role of MIF by employing novel MIF transgenic mice and new pharmacological MIF modulators. Therefore, this proposal will yield novel information concerning how the aging lung responds to respiratory pathogens, which could provide novel information to improve therapies for older people who succumb to respiratory infections.