Infection-induced inflammation and cerebral injury in preterm infants

Strunk, Tobias; Inder, Terrie E.; Wang, Xiaoyang; Burgner, David; Mallard, Carina; Levy, Ofer

doi:10.1016/s1473-3099(14)70710-8

Cited by 242 publications

(242 citation statements)

References 146 publications

(142 reference statements)

Supporting

Mentioning

219

Contrasting

Unclassified

Order By: Relevance

“…High circulating levels of inflammatory cytokines have been observed in very preterm infants exposed to intensive care (11) and have been repeatedly linked to worse outcomes such as bronchopulmonary dysplasia (12), white matter injury, and neurodevelopmental impairments (16). These results have led to speculations that the innate immune system of these infants is hyper-rather than hypo-responsive during the neonatal period (17).…”

Section: Discussionmentioning

confidence: 99%

Attenuated innate immune defenses in very premature neonates during the neonatal period

et al. 2015

View full text Add to dashboard Cite

Background: Antimicrobial responses have been shown to be profoundly attenuated in very preterm neonates when examined on cord blood. However, we lack data on these responses at the time these neonates are most vulnerable to infections. Methods: Multiple cytokine responses to two prototypic Toll-like receptor (TLR) agonists: lipopolysaccharide (LPS) (TLR4) and R848 (TLR7/8) were prospectively measured in preterm neonates born ≤30 wk of gestation (n = 50) during the first 28 d of age using whole blood and single-cell multiparameter flow cytometry assays. Results were compared to term neonates (n = 30) and adult controls (n = 25). results: In preterm neonates, LPS and R848 responses remained attenuated in both cord blood and in the first 28 d of age. These responses showed significant maturation over time after adjusting for gestational age and were confirmed in monocytes and dendritic cells on a per-cell basis. We detected no major contribution of chorioamnionitis, maternal antenatal corticosteroids or magnesium sulfate treatment, labor, or mode of delivery to the maturation of cytokine responses. conclusion: Innate immune antimicrobial defenses are profoundly attenuated developmentally in very preterm neonates during the neonatal period, suggesting that exogenous factors drive the sustained systemic inflammation that has been linked to increased morbidities in these infants.d espite improvements in neonatal health care, mortality from infections has continued to increase in very preterm neonates over the last two decades, owing to the improved survival of smaller and more vulnerable infants (1). However, the underlying immunological basis of their high morbidities and high vulnerability to sepsis remains poorly understood (2). To defend themselves against infection, neonates rely on first-line, innate immune defense mechanisms. These mechanisms include the detection of specific microbial molecular structures called pathogenassociated molecular patterns through specialized receptors termed pattern recognition receptors (PRR), but also other defense mechanisms such as phagocytosis and antigen presentation to the adaptive immune system.It is widely stated that the high risk of neonatal sepsis observed in these infants is due to immature immune defense mechanisms. However, data are lacking on the development of immune functions beyond measures performed on umbilical cord blood. Recent studies have reported reduced antigen-presenting receptor expression during the first week of age in infants born below 33 wk of gestation (3,4). In contrast, phagocytic functions in these infants are more comparable to term infants (5). Toll-like receptors (TLRs) play a predominant role as a major family of PRR that act as essential "detectors" in the recognition of microbial pathogens by the innate immune system. We and others have shown that TLR-induced cytokine immune reactivity are profoundly attenuated in cord blood of very preterm neonates and develops asynchronously over the last trimester of gestation (6-10). These infants als...

show abstract

Section: Discussionmentioning

confidence: 99%

Attenuated innate immune defenses in very premature neonates during the neonatal period

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Prompted by the growing epidemiologic and clinical evidence that bacteremia in human newborns, even in the absence of positive CSF cultures, is associated with subsequent CNS injury [2][3][4][5]30, 31], we tested the hypothesis that S. epidermidis bacteremia can induce brain injury and we characterized the potential roles of TLR2 in this process. To this end, we used an established neonatal S. epidermidis sepsis model [20] to demonstrate for the first time that (1) S. epidermidis bacteremia, in the absence of viable bacteria in the CSF, has a detrimental impact on the development of the neonatal brain via both rapid TLR2-dependent caspase-3 activation, as well as longer-term TLR2-independent pathways, culminating in reduced white and gray matter volumes; and (2) neonatal TLR2 is functional in host defense against S. epidermidis and serves to accelerate bacterial clearance.…”

Section: Discussionmentioning

confidence: 99%

“…Preterm birth is associated with a high risk of brain injury that can contribute to neurological disorders such as cerebral palsy, autism, and possibly schizophrenia [1,2]. Cerebral white-matter injury is the most common form of injury to the preterm brain and is associated with a high risk of neurodevelopmental impairment.…”

mentioning

confidence: 99%

“…In animal models, inflammation, such as that caused by systemic administration of lipopolysaccharide, induces cerebral white-matter injury similar to that seen in preterm human infants [3,7,8]. Fewer studies have addressed the ability of live bacteria to induce brain injury [9], and to our knowledge none of these have modeled this in newborn animals that express distinct immune function and susceptibility to brain injury [2,10].…”

mentioning

confidence: 99%

See 1 more Smart Citation

Staphylococcus epidermidisBacteremia Induces Brain Injury in Neonatal Mice via Toll-like Receptor 2-Dependent and -Independent Pathways

Bi¹,

Qiao²,

Bergelson³

et al. 2015

J Infect Dis.

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…Keywords: astrocyte; gap junction; Cx43; neonatal sepsis demonstrated that neonatal sepsis directly causes brain damage such as white matter lesions and periventricular leukomalacia, and is closely associated with a high rate of lethality in neonates [3] . Furthermore, survivors of neonatal sepsis often show severe long-term cognitive impairment and adverse neurologic outcomes [4][5][6][7] .…”

Section: Introductionmentioning

confidence: 99%

Decreased connexin 43 in astrocytes inhibits the neuroinflammatory reaction in an acute mouse model of neonatal sepsis

et al. 2015

View full text Add to dashboard Cite

Infection-induced inflammation and cerebral injury in preterm infants

Cited by 242 publications

References 146 publications

Attenuated innate immune defenses in very premature neonates during the neonatal period

Attenuated innate immune defenses in very premature neonates during the neonatal period

Staphylococcus epidermidisBacteremia Induces Brain Injury in Neonatal Mice via Toll-like Receptor 2-Dependent and -Independent Pathways

Decreased connexin 43 in astrocytes inhibits the neuroinflammatory reaction in an acute mouse model of neonatal sepsis

Contact Info

Product

Resources

About