title: Innate immune dysfunctions in aged mice facilitate the systemic dissemination of methicillin-resistant S. aureus.
abstract: Elderly humans show increased susceptibility to invasive staphylococcal disease after skin and soft tissue infection. However, it is not understood how host immunity changes with aging, and how that predisposes to invasive disease. In a model of severe skin infection, we showed that aged mice (16- to 20-month-old) exhibit dramatic bacterial dissemination compared with young adult mice (2-month-old). Bacterial dissemination was associated with significant reductions of CXCL1 (KC), polymorphonuclear cells (PMNs), and extracellular DNA traps (NETs) at the infection site. PMNs and primary skin fibroblasts isolated from aged mice showed decreased secretion of CXCL2 (MIP-2) and KC in response to MRSA, and in vitro analyses of mitochondrial functions revealed that the mitochondrial electron transport chain complex I plays a significant role in induction of chemokines in the cells isolated from young but not old mice. Additionally, PMNs isolated from aged mice have reduced ability to form NETs and to kill MRSA. Expression of nuclease by S. aureus led to increased bacterial systemic dissemination in young but not old mice, suggesting that defective NETs formation in elderly mice permitted nuclease and non-nuclease expressing S. aureus to disseminate equally well. Overall, these findings suggest that gross impairment of both skin barrier function and innate immunity contributes to the propensity for MRSA to disseminate in aged mice. Furthermore, the study indicates that contribution of bacterial factors to pathogenicity may vary with host age.
authors: Division of Pediatric Infectious Diseases, Cedars-Sinai Medical Center, Los Angeles, California, United States of America. tsengcw@cshs.org
authors: Ching Wen
authors: CW
authors: Tseng
authors: Pierre A
authors: PA
authors: Kyme
authors: Andrea
authors: A
authors: Arruda
authors: V Krishnan
authors: VK
authors: Ramanujan
authors: Wafa
authors: W
authors: Tawackoli
authors: George Y
authors: GY
authors: Liu
mesh_terms: D000375:Aging / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D018925:Chemokines / Q000378:metabolism; D003851:Deoxyribonucleases / Q000378:metabolism; D042967:Electron Transport Complex I / Q000378:metabolism; D005110:Extracellular Space / Q000378:metabolism / Q000382:microbiology; D005260:Female; D007113:Immunity, Innate; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus / Q000201:enzymology / Q000276:immunology / Q000502:physiology*; D051379:Mice; D009504:Neutrophils / Q000166:cytology / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D037521:Virulence Factors / Q000378:metabolism
chemical_list: D018925:Chemokines; D037521:Virulence Factors; D003851:Deoxyribonucleases; D042967:Electron Transport Complex I