title: Superantigens produced by catheter-associated Staphylococcus aureus elicit systemic inflammatory disease in the absence of bacteremia.
abstract: SAgs, produced by Staphylococcus aureus, play a major role in the pathogenesis of invasive staphylococcal diseases by inducing potent activation of the immune system. However, the role of SAgs, produced by S. aureus, associated with indwelling devices or tissues, are not known. Given the prevalence of device-associated infection with toxigenic S. aureus in clinical settings and the potency of SAgs, we hypothesized that continuous exposure to SAgs produced by catheter-associated S. aureus could have systemic consequences. To investigate these effects, we established a murine in vivo catheter colonization model. One centimeter long intravenous catheters were colonized with a clinical S. aureus isolate producing SAgs or isogenic S. aureus strains, capable or incapable of producing SAg. Catheters were subcutaneously implanted in age-matched HLA-DR3, B6, and AE(o) mice lacking MHC class II molecules and euthanized 7 d later. There was no evidence of systemic infection. However, in HLA-DR3 transgenic mice, which respond robustly to SSAgs, the SSAg-producing, but not the nonproducing strains, caused a transient increase in serum cytokine levels and a protracted expansion of splenic CD4(+) T cells expressing SSAg-reactive TCR Vβ8. Lungs, livers, and kidneys from these mice showed infiltration with CD4(+) and CD11b(+) cells. These findings were absent in B6 and AE(o) mice, which are known to respond poorly to SSAgs. Overall, our novel findings suggest that systemic immune activation elicited by SAgs, produced by S. aureus colonizing foreign bodies, could have clinical consequences in humans.
authors.affiliation: *Division of Clinical Microbiology, Department of Laboratory Medicine and Pathology, Divisions of Infectious Diseases and Rheumatology, Department of Medicine, and Department of Immunology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA; and Division of Infectious Diseases, Chung-Ang University College of Medicine, Seoul, Republic of Korea.
authors.forename: Jin-Won
authors.initials: JW
authors.lastname: Chung
authors.affiliation: *Division of Clinical Microbiology, Department of Laboratory Medicine and Pathology, Divisions of Infectious Diseases and Rheumatology, Department of Medicine, and Department of Immunology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA; and Division of Infectious Diseases, Chung-Ang University College of Medicine, Seoul, Republic of Korea.
authors.forename: Kerryl E
authors.initials: KE
authors.lastname: Greenwood-Quaintance
authors.affiliation: *Division of Clinical Microbiology, Department of Laboratory Medicine and Pathology, Divisions of Infectious Diseases and Rheumatology, Department of Medicine, and Department of Immunology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA; and Division of Infectious Diseases, Chung-Ang University College of Medicine, Seoul, Republic of Korea.
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Karau
authors.affiliation: *Division of Clinical Microbiology, Department of Laboratory Medicine and Pathology, Divisions of Infectious Diseases and Rheumatology, Department of Medicine, and Department of Immunology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA; and Division of Infectious Diseases, Chung-Ang University College of Medicine, Seoul, Republic of Korea.
authors.forename: Ashenafi
authors.initials: A
authors.lastname: Tilahun
authors.affiliation: *Division of Clinical Microbiology, Department of Laboratory Medicine and Pathology, Divisions of Infectious Diseases and Rheumatology, Department of Medicine, and Department of Immunology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA; and Division of Infectious Diseases, Chung-Ang University College of Medicine, Seoul, Republic of Korea.
authors.forename: Shahryar Rostamkolaei
authors.initials: SR
authors.lastname: Khaleghi
authors.affiliation: *Division of Clinical Microbiology, Department of Laboratory Medicine and Pathology, Divisions of Infectious Diseases and Rheumatology, Department of Medicine, and Department of Immunology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA; and Division of Infectious Diseases, Chung-Ang University College of Medicine, Seoul, Republic of Korea.
authors.forename: Vaidehi R
authors.initials: VR
authors.lastname: Chowdhary
authors.affiliation: *Division of Clinical Microbiology, Department of Laboratory Medicine and Pathology, Divisions of Infectious Diseases and Rheumatology, Department of Medicine, and Department of Immunology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA; and Division of Infectious Diseases, Chung-Ang University College of Medicine, Seoul, Republic of Korea.
authors.forename: Chella S
authors.initials: CS
authors.lastname: David
authors.affiliation: *Division of Clinical Microbiology, Department of Laboratory Medicine and Pathology, Divisions of Infectious Diseases and Rheumatology, Department of Medicine, and Department of Immunology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA; and Division of Infectious Diseases, Chung-Ang University College of Medicine, Seoul, Republic of Korea.
authors.forename: Robin
authors.initials: R
authors.lastname: Patel
authors.affiliation: *Division of Clinical Microbiology, Department of Laboratory Medicine and Pathology, Divisions of Infectious Diseases and Rheumatology, Department of Medicine, and Department of Immunology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA; and Division of Infectious Diseases, Chung-Ang University College of Medicine, Seoul, Republic of Korea rajagopalan.govindarajan@mayo.edu.
authors.forename: Govindarajan
authors.initials: G
authors.lastname: Rajagopalan
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D055499:Catheter-Related Infections / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D002408:Catheters, Indwelling; D004768:Enterotoxins / Q000096:biosynthesis* / Q000276:immunology; D017353:Gene Deletion; D006649:Histocompatibility Antigens / Q000235:genetics / Q000276:immunology; D006801:Humans; D007668:Kidney / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D008099:Liver / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D008168:Lung / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000276:immunology; D013154:Spleen / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D013203:Staphylococcal Infections / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D013211:Staphylococcus aureus / Q000276:immunology / Q000472:pathogenicity*; D018089:Superantigens / Q000096:biosynthesis* / Q000276:immunology
chemical_list: D004768:Enterotoxins; D006649:Histocompatibility Antigens; D016693:Receptors, Antigen, T-Cell, alpha-beta; D018089:Superantigens
keywords: HLA class II; T lymphocytes; cytokines; immunopathology; transgenic mice