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.