title: Enteric-delivered rapamycin enhances resistance of aged mice to pneumococcal pneumonia through reduced cellular senescence.
abstract: Rapamycin, a potent immunomodulatory drug, has shown promise in the amelioration of numerous age-associated diseases including cancer, Alzheimer's disease and cardiac hypertrophy. Yet the elderly, the population most likely to receive therapeutic rapamycin, are already at increased risk for infectious disease; thus concern exists that rapamycin may exacerbate age-associated immune dysfunctions and worsen infection outcomes. Herein, we examined the impact of enteric delivered rapamycin monotherapy (eRapa) on the susceptibility of aged (22-24month) C57BL/6 mice to Streptococcus pneumoniae, the leading bacterial cause of community-acquired pneumonia. Following challenge with S. pneumoniae, administration of eRapa conferred modest protection against mortality. Reduced mortality was the result of diminished lung damage rather than reduced bacterial burden. eRapa had no effect on basal levels of Interleukin (IL)-1α, IL-6, IL-10, IL-12p70, KC, Interferon-γ, Tumor necrosis factor α and Monocyte chemotactic protein-1 in whole lung homogenates or during pneumococcal pneumonia. Previously we have demonstrated that cellular senescence enhances permissiveness for bacterial pneumonia through increased expression of the bacterial ligands Laminin receptor (LR), Platelet-activating factor receptor (PAFr) and Cytokeratin 10 (K10). These proteins are co-opted by S. pneumoniae and other respiratory tract pathogens for host cell attachment during lung infection. UM-HET3 mice on eRapa had reduced lung cellular senescence as determined by levels of the senescence markers p21 and pRB, but not mH2A.1. Mice on eRapa also had marked reductions in PAFr, LR, and K10. We conclude that eRapa protected aged mice against pneumonia through reduced lung cellular senescence, which in turn, lowered bacterial ligand expression.
authors.affiliation: Department of Microbiology & Immunology, University of Texas Health Science Center San Antonio, San Antonio, TX 78229, United States.
authors.forename: Cecilia A
authors.initials: CA
authors.lastname: Hinojosa
authors.forename: Victoria
authors.initials: V
authors.lastname: Mgbemena
authors.forename: Sabrina
authors.initials: S
authors.lastname: Van Roekel
authors.forename: Steven N
authors.initials: SN
authors.lastname: Austad
authors.forename: Richard A
authors.initials: RA
authors.lastname: Miller
authors.forename: Santanu
authors.initials: S
authors.lastname: Bose
authors.forename: Carlos J
authors.initials: CJ
authors.lastname: Orihuela
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D016922:Cellular Senescence / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis; D004198:Disease Susceptibility; D004353:Drug Evaluation, Preclinical; D005260:Female; D008168:Lung / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011018:Pneumonia, Pneumococcal / Q000276:immunology / Q000382:microbiology / Q000473:pathology / Q000517:prevention & control*; D011971:Receptors, Immunologic / Q000378:metabolism; D020123:Sirolimus / Q000008:administration & dosage / Q000627:therapeutic use*; D013296:Streptococcus pneumoniae / Q000302:isolation & purification; D013608:Tablets, Enteric-Coated
chemical_list: D000900:Anti-Bacterial Agents; D016207:Cytokines; D011971:Receptors, Immunologic; D013608:Tablets, Enteric-Coated; D020123:Sirolimus