Animal Biosafety Level 3 Management Support, Lovelace Respiratory Research Institute, Albuquerque, NM 87108;
J Immunol. 2014 May 1;192(9):4273-83. doi: 10.4049/jimmunol.1303090. Epub 2014 Mar 26.
Pneumococcal infections remain a leading cause of death in persons ≥ 65 y of age. Recent reports have illustrated detrimental changes in the endoplasmic reticulum stress response or unfolded protein response in aging and age-related diseases; however, the relationship between aging, the unfolded protein response, and innate immune responses to Streptococcus pneumoniae has not been fully elucidated. Our results illustrate that stimulator of IFN genes-mediated production of IFN-β during S. pneumoniae infection is decreased in aged hosts. Enhanced endoplasmic reticulum stress in response to S. pneumoniae augmented inositol-requiring protein 1/X-box binding protein 1-mediated production of autophagy-related gene 9 (Atg9a). Knockdown of Atg9a or treatment with gemcitabine HCl resulted in enhanced stimulator of IFN genes-mediated production of IFN-β by aged macrophages. Consecutive treatments with gemcitabine during in vivo S. pneumoniae infection decreased morbidity and mortality in aged hosts, which was associated with decreased Atg9a expression, increased IFN-β production, and improved bacterial clearance from lung tissue. Taken together, data presented in this study provide new evidence as to why older persons are more susceptible to S. pneumoniae, and provide a possible mechanism to enhance these responses, thereby decreasing morbidity and mortality in this population.
肺炎球菌感染仍然是导致≥65 岁人群死亡的主要原因。最近的报告表明，内质网应激反应或未折叠蛋白反应在衰老和与年龄相关的疾病中发生了有害变化；然而，衰老、未折叠蛋白反应与肺炎链球菌固有免疫反应之间的关系尚未完全阐明。我们的结果表明，在肺炎球菌感染期间，IFN 基因刺激物介导的 IFN-β产生在老年宿主中减少。针对肺炎球菌的内质网应激增强，导致 1-肌醇需求蛋白 1/X 盒结合蛋白 1 介导的自噬相关基因 9（Atg9a）产生增加。Atg9a 的敲低或用盐酸吉西他滨处理导致老年巨噬细胞中 IFN 基因刺激物介导的 IFN-β产生增加。在体内肺炎球菌感染期间连续用盐酸吉西他滨治疗可降低老年宿主的发病率和死亡率，这与 Atg9a 表达减少、IFN-β 产生增加以及肺组织中细菌清除率提高有关。总之，本研究提供的新证据表明，为什么老年人更容易感染肺炎球菌，并提供了一种增强这些反应的可能机制，从而降低该人群的发病率和死亡率。
