Dan Bi1, Lili Qiao2, Ilana Bergelson3, C Joakim Ek4, Luqi Duan1, Xiaoli Zhang1, Anna-Maj Albertsson4, Matthew Pettengill3, Kenny Kronforst5, Jana Ninkovic6, Donald Goldmann3, Anders Janzon4, Henrik Hagberg7, Xiaoyang Wang1, Carina Mallard8, Ofer Levy3. 1. Department of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Sweden Department of Pediatrics, Third Affiliated Hospital, Zhengzhou University. 2. Department of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Sweden Department of Pediatrics, Song Jiang Central Hospital, Shanghai, China. 3. Division of Infectious Diseases, Department of Medicine, Boston Children's Hospital Harvard Medical School, Boston, Massachusetts. 4. Department of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Sweden. 5. Department of Pediatrics, Division of Neonatology, Lurie Children's Hospital of Chicago and Prentice Women's Hospital, Feinberg School of Medicine, Northwestern University, Illinois. 6. 3M Corporate Research Materials Laboratory, St. Paul, Minnesota. 7. 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. 8. 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.
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.
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.
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