期刊
JOURNAL OF IMMUNOLOGY
卷 192, 期 9, 页码 4273-4283出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1303090
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- NIA NIH HHS [K01AG034999, R21 AG044755, K01 AG034999, L30 AG043118, R21AG044755] Funding Source: Medline
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-b during S. pneumoniae infection is decreased in aged hosts. Enhanced endoplasmic reticulum stress in response to S. pneumoniae augmented inositolrequiring 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-b 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-b 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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