title: Manipulation of Autophagy in Phagocytes Facilitates Staphylococcus aureus Bloodstream Infection.
abstract: The capacity for intracellular survival within phagocytes is likely a critical factor facilitating the dissemination of Staphylococcus aureus in the host. To date, the majority of work on S. aureus-phagocyte interactions has focused on neutrophils and, to a lesser extent, macrophages, yet we understand little about the role played by dendritic cells (DCs) in the direct killing of this bacterium. Using bone marrow-derived DCs (BMDCs), we demonstrate for the first time that DCs can effectively kill S. aureus but that certain strains of S. aureus have the capacity to evade DC (and macrophage) killing by manipulation of autophagic pathways. Strains with high levels of Agr activity were capable of causing autophagosome accumulation, were not killed by BMDCs, and subsequently escaped from the phagocyte, exerting significant cytotoxic effects. Conversely, strains that exhibited low levels of Agr activity failed to accumulate autophagosomes and were killed by BMDCs. Inhibition of the autophagic pathway by treatment with 3-methyladenine restored the bactericidal effects of BMDCs. Using an in vivo model of systemic infection, we demonstrated that the ability of S. aureus strains to evade phagocytic cell killing and to survive temporarily within phagocytes correlated with persistence in the periphery and that this effect is critically Agr dependent. Taken together, our data suggest that strains of S. aureus exhibiting high levels of Agr activity are capable of blocking autophagic flux, leading to the accumulation of autophagosomes. Within these autophagosomes, the bacteria are protected from phagocytic killing, thus providing an intracellular survival niche within professional phagocytes, which ultimately facilitates dissemination.
authors.affiliation: Host Pathogen Interactions Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
authors.forename: Kate M
authors.initials: KM
authors.lastname: O'Keeffe
authors.affiliation: Host Pathogen Interactions Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
authors.forename: Mieszko M
authors.initials: MM
authors.lastname: Wilk
authors.affiliation: Host Pathogen Interactions Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
authors.forename: John M
authors.initials: JM
authors.lastname: Leech
authors.affiliation: Host Pathogen Interactions Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
authors.forename: Alison G
authors.initials: AG
authors.lastname: Murphy
authors.affiliation: Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath, United Kingdom.
authors.forename: Maisem
authors.initials: M
authors.lastname: Laabei
authors.affiliation: Microbiology Department, Moyne Institute of Preventative Medicine, Trinity College Dublin, Dublin, Ireland.
authors.forename: Ian R
authors.initials: IR
authors.lastname: Monk
authors.affiliation: Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath, United Kingdom.
authors.forename: Ruth C
authors.initials: RC
authors.lastname: Massey
authors.affiliation: Institute for Infection and Immunity, St. George's, University of London, London, United Kingdom.
authors.forename: Jodi A
authors.initials: JA
authors.lastname: Lindsay
authors.affiliation: Microbiology Department, Moyne Institute of Preventative Medicine, Trinity College Dublin, Dublin, Ireland.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Foster
authors.affiliation: Microbiology Department, Moyne Institute of Preventative Medicine, Trinity College Dublin, Dublin, Ireland.
authors.forename: Joan A
authors.initials: JA
authors.lastname: Geoghegan
authors.affiliation: Host Pathogen Interactions Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland rachel.mcloughlin@tcd.ie.
authors.forename: Rachel M
authors.initials: RM
authors.lastname: McLoughlin
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology*; D016470:Bacteremia / Q000378:metabolism / Q000382:microbiology; D001426:Bacterial Proteins / Q000378:metabolism*; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000382:microbiology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000382:microbiology*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013203:Staphylococcal Infections / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D013211:Staphylococcus aureus / Q000276:immunology; D015534:Trans-Activators / Q000378:metabolism*
chemical_list: C095698:Agr protein, Staphylococcus aureus; D001426:Bacterial Proteins; D015534:Trans-Activators