title: A potential new pathway for Staphylococcus aureus dissemination: the silent survival of S. aureus phagocytosed by human monocyte-derived macrophages.
abstract: Although considered to be an extracellular pathogen, Staphylococcus aureus is able to invade a variety of mammalian, non-professional phagocytes and can also survive engulfment by professional phagocytes such as neutrophils and monocytes. In both of these cell types S. aureus promptly escapes from the endosomes/phagosomes and proliferates within the cytoplasm, which quickly leads to host cell death. In this report we show that S. aureus interacted with human monocyte-derived macrophages in a very different way to those of other mammalian cells. Upon phagocytosis by macrophages, S. aureus persisted intracellularly in vacuoles for 3-4 days before escaping into the cytoplasm and causing host cell lysis. Until the point of host cell lysis the infected macrophages showed no signs of apoptosis or necrosis and were functional. They were able to eliminate intracellular staphylococci if prestimulated with interferon-gamma at concentrations equivalent to human therapeutic doses. S. aureus survival was dependent on the alternative sigma factor B as well as the global regulator agr, but not SarA. Furthermore, isogenic mutants deficient in alpha-toxin, the metalloprotease aureolysin, protein A, and sortase A were efficiently killed by macrophages upon phagocytosis, although with different kinetics. In particular alpha-toxin was a key effector molecule that was essential for S. aureus intracellular survival in macrophages. Together, our data indicate that the ability of S. aureus to survive phagocytosis by macrophages is determined by multiple virulence factors in a way that differs considerably from its interactions with other cell types. S. aureus persists inside macrophages for several days without affecting the viability of these mobile cells which may serve as vehicles for the dissemination of infection.
authors.affiliation: Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland. staphaureus@gmail.com
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Kubica
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Guzik
authors.forename: Joanna
authors.initials: J
authors.lastname: Koziel
authors.forename: Miroslaw
authors.initials: M
authors.lastname: Zarebski
authors.forename: Walter
authors.initials: W
authors.lastname: Richter
authors.forename: Barbara
authors.initials: B
authors.lastname: Gajkowska
authors.forename: Anna
authors.initials: A
authors.lastname: Golda
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Maciag-Gudowska
authors.forename: Klaudia
authors.initials: K
authors.lastname: Brix
authors.forename: Les
authors.initials: L
authors.lastname: Shaw
authors.forename: Timothy
authors.initials: T
authors.lastname: Foster
authors.forename: Jan
authors.initials: J
authors.lastname: Potempa
mesh_terms: D001770:Blood Bactericidal Activity; D006801:Humans; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology; D009000:Monocytes / Q000276:immunology* / Q000382:microbiology; D010587:Phagocytosis; D013211:Staphylococcus aureus / Q000502:physiology*