title: S. aureus blocks efferocytosis of neutrophils by macrophages through the activity of its virulence factor alpha toxin.
abstract: Bacterial pneumonia, such as those caused by Staphylococcus aureus, is associated with an influx of inflammatory neutrophils into the lung tissue and airways. Regulation and clearance of recruited neutrophils is essential for preventing tissue damage by "friendly fire", a responsibility of macrophages in a process called efferocytosis. We hypothesized that S. aureus impairs efferocytosis by alveolar macrophages (AMs) through the activity of the secreted virulence factor alpha toxin (AT), which has been implicated in altering the antimicrobial function of AMs. Infection of mice lacking AMs resulted in significantly increased numbers of neutrophils in the lung, while clearance of neutrophils delivered intranasally into uninfected mice was reduced in AM depleted animals. In vitro, sublytic levels of AT impaired uptake of apoptotic neutrophils by purified AMs. In vivo, the presence of AT reduced uptake of neutrophils by AMs. Differential uptake of neutrophils was not due to changes in either the CD47/CD172 axis or CD36 levels. AT significantly reduced lung expression of CCN1 and altered AM surface localization of DD1α, two proteins known to influence efferocytosis. We conclude that AT may contribute to tissue damage during S. aureus pneumonia by inhibiting the ability of AM to clear neutrophils at the site of infection.
authors.affiliation: Department of Infectious Disease, Medimmune, LLC One MedImmune Way, Gaithersburg, MD 20878, USA.
authors.forename: Taylor S
authors.initials: TS
authors.lastname: Cohen
authors.affiliation: Department of Infectious Disease, Medimmune, LLC One MedImmune Way, Gaithersburg, MD 20878, USA.
authors.forename: Omari
authors.initials: O
authors.lastname: Jones-Nelson
authors.affiliation: Department of Infectious Disease, Medimmune, LLC One MedImmune Way, Gaithersburg, MD 20878, USA.
authors.forename: Meghan
authors.initials: M
authors.lastname: Hotz
authors.affiliation: Department of Translational Science, Medimmune, LLC One MedImmune Way, Gaithersburg, MD 20878, USA.
authors.forename: Lily
authors.initials: L
authors.lastname: Cheng
authors.affiliation: Department of Dermatology, John Hopkins University School of Medicine, Baltimore MD 21231, USA.
authors.forename: Lloyd S
authors.initials: LS
authors.lastname: Miller
authors.affiliation: Department of Infectious Disease, Medimmune, LLC One MedImmune Way, Gaithersburg, MD 20878, USA.
authors.forename: JoAnn
authors.initials: J
authors.lastname: Suzich
authors.affiliation: Department of Infectious Disease, Medimmune, LLC One MedImmune Way, Gaithersburg, MD 20878, USA.
authors.forename: C Kendall
authors.initials: CK
authors.lastname: Stover
authors.affiliation: Department of Infectious Disease, Medimmune, LLC One MedImmune Way, Gaithersburg, MD 20878, USA.
authors.forename: Bret R
authors.initials: BR
authors.lastname: Sellman
mesh_terms: D000818:Animals; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism; D051928:CD47 Antigen / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement; D055515:Cysteine-Rich Protein 61 / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D008264:Macrophages / Q000276:immunology*; D008565:Membrane Proteins / Q000378:metabolism; D055624:Methicillin-Resistant Staphylococcus aureus / Q000472:pathogenicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000276:immunology* / Q000502:physiology; D018410:Pneumonia, Bacterial / Q000276:immunology* / Q000382:microbiology; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism; D037521:Virulence Factors / Q000633:toxicity*
chemical_list: C491850:CCN1 protein, mouse; D018955:CD36 Antigens; D051928:CD47 Antigen; D055515:Cysteine-Rich Protein 61; D008565:Membrane Proteins; C501922:Sirpa protein, mouse; D011971:Receptors, Immunologic; D037521:Virulence Factors; C548983:Vsir protein, mouse