Staphylococcus epidermidisBacteremia 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.

TLR2-mediated leukocyte trafficking to the developing brain

“…In addition, the strong proinflammatory TLR4 ligand, LPS, did not result in pleocytosis. Specific TLR2mediated effects may be of importance for neurologic outcome in the newborn, as we have previously shown that repeated stimulation of TLR2 results in impaired brain development [14] and that the gram-positive bacteria Staphylococcus epidermidis induces brain injury in neonatal mice, partly via TLR2-dependent pathways [27]. Furthermore, TLR2deficient mice are protected from neonatal hypoxia-ischemia, which further supports the importance of TLR2 in neonatal brain injury [13].…”

Staphylococcus epidermidis Sensitizes Perinatal Hypoxic-Ischemic Brain Injury in Male but Not Female Mice

“…We have previously reported that S. epidermidis infection 14 h prior to HI in neonatal (PND4) mice sensitizes the brain to cerebral injury (14) and that intravenous injection of S. epidermidis at PND0 impairs brain development (26). S. epidermidis is known to activate TLR2 (27), but S. epidermidis induction of neonatal brain injury is both TLR2 dependent and independent (26). Furthermore, innate immune responses to S. epidermidis in preterm infants is known to be age-dependent (28).…”

Pentoxifylline inhibits TLR- and inflammasome-mediated in vitro inflammatory cytokine production in human blood with greater efficacy and potency in newborns

“…Neonatal inflammation is driven in part by TLR signaling and can contribute to host defense against infection (27)(28)(29)(30). However, TLR-mediated cytokine induction can also contribute to pathology and disease, including inflammatory diseases of early life such as sepsis, BPD and perinatal brain injury (31)(32)(33). PTX, a nonspecific phosphodiesterase inhibitor that decreases transcription of proinflammatory cytokines, is a promising anti-inflammatory candidate for neonates.…”