title: Anti-pneumococcal deficits of monocyte-derived macrophages from the advanced-age, frail elderly and related impairments in PI3K-AKT signaling.
abstract: The advanced-age, frail elderly are especially vulnerable to developing pneumococcal infection and disease. Macrophages are critical mediators in the defence against Streptococcus pneumoniae at the upper respiratory tract, however, little is known of their anti-pneumococcal capacity in the elderly. Herein we demonstrate that monocyte-derived macrophages (MDMs) from the advanced-age, frail elderly produce less TNF, IL-6, IL-1β and IL-8 in response to heat-killed S. pneumoniae, which does not appear to be related to mRNA stability or decay. Furthermore, despite maintaining the ability to bind and phagocytose bacteria, MDMs from these individuals have a reduced capacity to kill S. pneumoniae. These defects parallel reduced PI3K-AKT signaling, which can significantly abrogate bacterial killing, but does not affect cytokine responses. Since macrophages are critical in the defence against S. pneumoniae, this study adds valuable insight into the susceptibility of the elderly to pneumococcal disease and highlights the PI3K-AKT signaling pathway as a potential therapeutic target.
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada; Institute for Infectious Diseases Research, McMaster University, Hamilton, Ontario, Canada. Electronic address: cversch@mcmaster.ca.
authors.forename: Chris P
authors.initials: CP
authors.lastname: Verschoor
authors.affiliation: Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada. Electronic address: johnsj48@mcmaster.ca.
authors.forename: Jennie
authors.initials: J
authors.lastname: Johnstone
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada; Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada; Institute for Infectious Diseases Research, McMaster University, Hamilton, Ontario, Canada. Electronic address: loebm@mcmaster.ca.
authors.forename: Mark
authors.initials: M
authors.lastname: Loeb
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada; Institute for Infectious Diseases Research, McMaster University, Hamilton, Ontario, Canada. Electronic address: bramsonj@mcmaster.ca.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Bramson
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada; Institute for Infectious Diseases Research, McMaster University, Hamilton, Ontario, Canada. Electronic address: bowdish@mcmaster.ca.
authors.forename: Dawn M E
authors.initials: DM
authors.lastname: Bowdish
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000730:Androstadienes / Q000494:pharmacology; D002867:Chromones / Q000494:pharmacology; D004198:Disease Susceptibility / Q000276:immunology; D016330:Frail Elderly; D006801:Humans; D053583:Interleukin-1beta / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis; D008264:Macrophages / Q000276:immunology*; D008875:Middle Aged; D009025:Morpholines / Q000494:pharmacology; D010587:Phagocytosis / Q000276:immunology; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011018:Pneumonia, Pneumococcal / Q000276:immunology* / Q000382:microbiology / Q000401:mortality; D051057:Proto-Oncogene Proteins c-akt / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D013296:Streptococcus pneumoniae / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D000077191:Wortmannin; D055815:Young Adult
chemical_list: D000730:Androstadienes; D002867:Chromones; D053583:Interleukin-1beta; D015850:Interleukin-6; D016209:Interleukin-8; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D014409:Tumor Necrosis Factor-alpha; D000077191:Wortmannin; C508606:CXCL8 protein, human; C508585:IL1B protein, human; C508600:IL6 protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
keywords: AKT; Aging; Cytokine; Macrophage; Streptococcus pneumoniae