title: Staphylococcus epidermidis Bacteremia Induces Brain Injury in Neonatal Mice via Toll-like Receptor 2-Dependent and -Independent Pathways.
abstract: BACKGROUND
  Staphylococcus epidermidis causes late-onset sepsis in preterm infants. Staphylococcus epidermidis activates host responses in part via Toll-like receptor 2 (TLR2). Epidemiologic studies link bacteremia and neonatal brain injury, but direct evidence is lacking.
  
  
  METHODS
  Wild-type and TLR2-deficient (TLR2-/-) mice were injected intravenously with S. epidermidis at postnatal day 1 prior to measuring plasma and brain cytokine and chemokine levels, bacterial clearance, brain caspase-3 activation, white/gray matter volume, and innate transcriptome.
  
  
  RESULTS
  Staphylococcus epidermidis bacteremia spontaneously resolved over 24 hours without detectable bacteria in the cerebrospinal fluid (CSF). TLR2-/- mice demonstrated delayed S. epidermidis clearance from blood, spleen, and liver. Staphylococcus epidermidis increased the white blood cell count in the CSF, increased interleukin 6, interleukin 12p40, CCL2, and CXCL1 concentrations in plasma; increased the CCL2 concentration in the brain; and caused rapid (within 6 hours) TLR2-dependent brain activation of caspase-3 and TLR2-independent white matter injury.
  
  
  CONCLUSIONS
  Staphylococcus epidermidis bacteremia, in the absence of bacterial entry into the CSF, impairs neonatal brain development. Staphylococcus epidermidis bacteremia induced both TLR2-dependent and -independent brain injury, with the latter occurring in the absence of TLR2, a condition associated with an increased bacterial burden. Our study indicates that the consequences of transient bacteremia in early life may be more severe than commonly appreciated, and our findings may inform novel approaches to reduce bacteremia-associated brain injury.
authors.affiliation: Department of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Sweden Department of Pediatrics, Third Affiliated Hospital, Zhengzhou University.
authors.forename: Dan
authors.initials: D
authors.lastname: Bi
authors.affiliation: Department of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Sweden Department of Pediatrics, Song Jiang Central Hospital, Shanghai, China.
authors.forename: Lili
authors.initials: L
authors.lastname: Qiao
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Boston Children's Hospital Harvard Medical School, Boston, Massachusetts.
authors.forename: Ilana
authors.initials: I
authors.lastname: Bergelson
authors.affiliation: Department of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Sweden.
authors.forename: C Joakim
authors.initials: CJ
authors.lastname: Ek
authors.affiliation: Department of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Sweden Department of Pediatrics, Third Affiliated Hospital, Zhengzhou University.
authors.forename: Luqi
authors.initials: L
authors.lastname: Duan
authors.affiliation: Department of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Sweden Department of Pediatrics, Third Affiliated Hospital, Zhengzhou University.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Sweden.
authors.forename: Anna-Maj
authors.initials: AM
authors.lastname: Albertsson
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Boston Children's Hospital Harvard Medical School, Boston, Massachusetts.
authors.forename: Matthew
authors.initials: M
authors.lastname: Pettengill
authors.affiliation: Department of Pediatrics, Division of Neonatology, Lurie Children's Hospital of Chicago and Prentice Women's Hospital, Feinberg School of Medicine, Northwestern University, Illinois.
authors.forename: Kenny
authors.initials: K
authors.lastname: Kronforst
authors.affiliation: 3M Corporate Research Materials Laboratory, St. Paul, Minnesota.
authors.forename: Jana
authors.initials: J
authors.lastname: Ninkovic
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Boston Children's Hospital Harvard Medical School, Boston, Massachusetts.
authors.forename: Donald
authors.initials: D
authors.lastname: Goldmann
authors.affiliation: Department of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Janzon
authors.affiliation: Department of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Sweden Department of Obstetrics and Gynecology, Sahlgrenska Academy, University of Gothenburg, Sweden Centre for the Developing Brain, Department of Perinatal Imaging and Health, King's College London, United Kingdom.
authors.forename: Henrik
authors.initials: H
authors.lastname: Hagberg
authors.affiliation: Department of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Sweden Department of Pediatrics, Third Affiliated Hospital, Zhengzhou University.
authors.forename: Xiaoyang
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Sweden Centre for the Developing Brain, Department of Perinatal Imaging and Health, King's College London, United Kingdom.
authors.forename: Carina
authors.initials: C
authors.lastname: Mallard
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Boston Children's Hospital Harvard Medical School, Boston, Massachusetts.
authors.forename: Ofer
authors.initials: O
authors.lastname: Levy
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D016470:Bacteremia / Q000473:pathology*; D001930:Brain Injuries / Q000382:microbiology*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D018932:Chemokine CCL2 / Q000097:blood; D054360:Chemokine CXCL1 / Q000097:blood; D015169:Colony Count, Microbial; D004195:Disease Models, Animal; D053762:Interleukin-12 Subunit p40 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008099:Liver / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013154:Spleen / Q000382:microbiology; D013212:Staphylococcus epidermidis / Q000302:isolation & purification*; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; D053762:Interleukin-12 Subunit p40; D015850:Interleukin-6; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; C505409:Casp3 protein, mouse; D053148:Caspase 3
keywords: Staphylococcus epidermidis; Toll-like receptor; brain injury; preterm