title: Neutrophil crawling in capillaries; a novel immune response to Staphylococcus aureus.
abstract: Methicillin-resistant Staphylococcus aureus (MRSA), particularly the USA300 strain, is a highly virulent pathogen responsible for an increasing number of skin and soft tissue infections globally. Furthermore, MRSA-induced soft tissue infections can rapidly progress into life-threatening conditions, such as sepsis and necrotizing fasciitis. The importance of neutrophils in these devastating soft tissue infections remains ambiguous, partly because of our incomplete understanding of their behaviour. Spinning disk confocal microscopy was used to visualize the behaviour of GR1-labelled neutrophils in subcutaneous tissue in response to GFP-expressing MRSA attached to a foreign particle (agarose bead). We observed significant directional neutrophil recruitment towards the S. aureus agarose bead but not a control agarose bead. A significant increase in neutrophil crawling within the capillaries surrounding the infectious nidus was noted, with impaired capillary perfusion in these vessels and increased parenchymal cell death. No neutrophils were able to emigrate from capillaries. The crawling within these capillaries was mediated by the β(2) and α(4) integrins and blocking these integrins 2 hours post infection eliminated neutrophil crawling, improved capillary perfusion, reduced cell death and reduced lesion size. Blocking prior to infection increased pathology. Neutrophil crawling within capillaries during MRSA soft tissue infections, while potentially contributing to walling off or preventing early dissemination of the pathogen, resulted in impaired perfusion and increased tissue injury with time.
authors.affiliation: The Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Mark Geoffrey
authors.initials: MG
authors.lastname: Harding
authors.affiliation: The Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada; Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Kunyan
authors.initials: K
authors.lastname: Zhang
authors.affiliation: The Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada; Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: John
authors.initials: J
authors.lastname: Conly
authors.affiliation: The Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada; Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada; Department of Critical Care, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Paul
authors.initials: P
authors.lastname: Kubes
mesh_terms: D000818:Animals; D002196:Capillaries / Q000473:pathology; D016923:Cell Death / Q000276:immunology; D017714:Community-Acquired Infections / Q000276:immunology; D008297:Male; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration / Q000276:immunology*; D009504:Neutrophils / Q000166:cytology / Q000276:immunology*; D012867:Skin / Q000473:pathology; D013207:Staphylococcal Skin Infections / Q000276:immunology* / Q000473:pathology; D013211:Staphylococcus aureus