Age-enhanced endoplasmic reticulum stress contributes to increased Atg9A inhibition of STING-mediated IFN-β production during Streptococcus pneumoniae infection

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / immunology*
  • Animals
  • Autophagy-Related Proteins
  • Blotting, Western
  • Cells, Cultured
  • Endoplasmic Reticulum Stress / immunology*
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Flow Cytometry
  • Immunoprecipitation
  • Interferon-beta / biosynthesis*
  • Interferon-beta / immunology
  • Male
  • Membrane Proteins / immunology*
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Pneumococcal Infections / immunology*
  • Pneumococcal Infections / metabolism
  • RNA, Small Interfering
  • Real-Time Polymerase Chain Reaction
  • Transfection
  • Vesicular Transport Proteins


  • Atg9A protein, mouse
  • Autophagy-Related Proteins
  • Membrane Proteins
  • RNA, Small Interfering
  • Sting1 protein, mouse
  • Vesicular Transport Proteins
  • Interferon-beta