title: Age-enhanced endoplasmic reticulum stress contributes to increased Atg9A inhibition of STING-mediated IFN-β production during Streptococcus pneumoniae infection.
abstract: 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.
authors.affiliation: Animal Biosafety Level 3 Management Support, Lovelace Respiratory Research Institute, Albuquerque, NM 87108;
authors.forename: Dana N
authors.initials: DN
authors.lastname: Mitzel
authors.forename: Virginia
authors.initials: V
authors.lastname: Lowry
authors.forename: Anushree C
authors.initials: AC
authors.lastname: Shirali
authors.forename: Yushi
authors.initials: Y
authors.lastname: Liu
authors.forename: Heather W
authors.initials: HW
authors.lastname: Stout-Delgado
mesh_terms: D000375:Aging / Q000276:immunology*; D000818:Animals; D000071183:Autophagy-Related Proteins; D015153:Blotting, Western; D002478:Cells, Cultured; D059865:Endoplasmic Reticulum Stress / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D047468:Immunoprecipitation; D016899:Interferon-beta / Q000096:biosynthesis* / Q000276:immunology; D008297:Male; D008565:Membrane Proteins / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D011008:Pneumococcal Infections / Q000276:immunology* / Q000378:metabolism; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D014162:Transfection; D033921:Vesicular Transport Proteins; D000099197:STING Protein
chemical_list: D000071183:Autophagy-Related Proteins; D016899:Interferon-beta; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D033921:Vesicular Transport Proteins; C549015:Atg9A protein, mouse; C530855:Sting1 protein, mouse; D000099197:STING Protein