Age-enhanced endoplasmic reticulum stress contributes to increased Atg9A inhibition of STING-mediated IFN-β production during Streptococcus pneumoniae infection.
Age-enhanced endoplasmic reticulum stress contributes to increased Atg9A inhibition of STING-mediated IFN-β production during Streptococcus pneumoniae infection.
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DOI：
10.4049/jimmunol.1303090
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发表时间：
2014-05-01
期刊：
影响因子：
--
通讯作者：
Stout-Delgado HW
中科院分区：
文献类型：
--
作者：
Mitzel DN;Lowry V;Shirali AC;Liu Y;Stout-Delgado HW
肺炎球菌感染仍然是≥65岁人群死亡的主要原因。最近的报道表明，在衰老和与年龄相关的疾病中，内质网应激反应或未折叠蛋白反应(UPR)发生了有害的变化；然而，衰老、UPR和肺炎链球菌的天然免疫反应之间的关系尚未完全阐明。我们的结果表明，在肺炎链球菌感染的老年宿主中，刺痛介导的干扰素β的产生减少。肺炎链球菌增强内质网应激增强IRE1/XBP1介导的Atg9a产生。抑制atg9a或用盐酸吉西他滨治疗可增加老化巨噬细胞刺激性干扰素β的产生。在体内肺炎链球菌感染期间连续使用吉西他滨可降低老年宿主的发病率和死亡率，这与降低atg9a的表达、增加干扰素β的产生以及改善肺组织细菌的清除有关。综上所述，这项研究中提供的数据为老年人更容易感染肺炎链球菌提供了新的证据，并提供了一种可能的机制来增强这些反应，从而降低这一人群的发病率和死亡率。
Pneumococcal infections remain a leading cause of death in persons ≥ 65 years of age. Recent reports have illustrated detrimental changes in the ER stress response or unfolded protein response (UPR) in aging and age-related diseases; however the relationship between aging, the UPR, and innate immune responses to Streptococcus pneumoniae has not been fully elucidated. Our results illustrate that STING mediated production of IFNβ during S. pneumoniae infection is decreased in aged hosts. Enhanced ER stress in response to S. pne umoniae augmented IRE1/XBP1 mediated production of Atg9a. Knockdown of Atg9a or treatment with gemcitabine HCL resulted in enhanced STING mediated production of IFNβ 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 IFNβ 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.
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DOI：
10.1084/jem.20082874
发表时间：
2009-08-31
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
McWhirter SM;Barbalat R;Monroe KM;Fontana MF;Hyodo M;Joncker NT;Ishii KJ;Akira S;Colonna M;Chen ZJ;Fitzgerald KA;Hayakawa Y;Vance RE
通讯作者：
Vance RE
影响因子：
3.7
作者：
Martens P;Worm SW;Lundgren B;Konradsen HB;Benfield T
通讯作者：
Benfield T
影响因子：
4.4
作者：
Mancuso, Giuseppe;Midiri, Angelina;Teti, Giuseppe
通讯作者：
Teti, Giuseppe
影响因子：
4.8
作者：
Mayer, M;Kies, U;Buchner, J
通讯作者：
Buchner, J
影响因子：
10.5
作者：
Marciniak, SJ;Yun, CY;Ron, D
通讯作者：
Ron, D