Table of Contents Author Guidelines Submit a Manuscript
Table of Contents Alerts

To receive news and publication updates for Neurology Research International, enter your email address in the box below.

Neurology Research International
Volume 2012, Article ID 102153, 6 pages
http://dx.doi.org/10.1155/2012/102153
Review Article

Infection-Induced Vulnerability of Perinatal Brain Injury

Carina Mallard1 and Xiaoyang Wang1,2

1Department of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, P.O. Box 432, 40530 Göteborg, Sweden
2Department of Pediatrics, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China

Received 7 September 2011; Accepted 5 October 2011

Academic Editor: Jianrong Li

Copyright © 2012 Carina Mallard and Xiaoyang Wang. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

A growing body of evidence demonstrates that susceptibility and progression of both acute and chronic central nervous system disease in the newborn is closely associated with an innate immune response that can manifest from either direct infection and/or infection-triggered damage. A common feature of many of these diseases is the systemic exposure of the neonate to bacterial infections that elicit brain inflammation. In recent years, the importance of innate immune receptors in newborn brain injury, the so-called Toll-like receptors, has been demonstrated. In this paper we will discuss how neonatal sepsis, with particular emphasis on Escherichia coli, coagulase-negative staphylococci, and group B streptococcal infections in preterm infants, and Toll-like receptor-mediated inflammation can increase the vulnerability of the newborn brain to injury.

1. Introduction

Perinatal brain injury represents a significant clinical problem [1]. A growing body of evidence demonstrates that susceptibility and progression of both acute and chronic central nervous system (CNS) disease is closely associated with an innate immune response that can manifest from either direct infection and/or infection-triggered damage [2]. A common feature of these diseases is the systemic activation of inflammatory mediators, which via the blood can disrupt the blood-brain barrier, affect the circumventricular organs in the brain (which lack a blood-brain barrier), or interact with the brain endothelium, thereby eliciting brain inflammation [3]. Furthermore, the presence of activated inflammatory cells derived from systemic circulation or from dormant brain resident populations is a key feature of many CNS diseases. More recently, the importance of innate immune receptors in CNS injury, the so-called Toll-like receptors (TLRs), has also been emphasized. In this paper we will focus on how neonatal sepsis and TLR-mediated inflammation increase the vulnerability of the newborn brain.

2. Neonatal Sepsis and Brain Injury

Infants with sepsis have an increased incidence of cerebral palsy [4] and white matter abnormalities [5–11]. In a large study of 6093 extremely low birth weight (<1000 g) infants, those who were infected (including early-onset sepsis, suspected sepsis (culture negative), and had necrotizing enterocolitis (NEC)) were more likely to have cerebral palsy than children who did not have a neonatal infection [12]. In another recent large sample-size study involving 1155 infants born at 23 to 27 weeks gestation, it was found that children who had both late bacteremia (positive blood culture result after the first postnatal week) and surgical NEC were at increased risk of diparetic cerebral palsy compared with children who had neither [13]. Moreover, by comparing outcomes of 150 infants with periventricular leukomalacia (PVL) with controls matched for gestational age, it was found that infants with bacterial sepsis were twice as likely to develop PVL, and those with meningitis were almost four times as likely to develop white matter disease [14]. Similar findings were noted in a smaller case-control study, where associations between cerebral palsy, clinical chorioamnionitis and sepsis were demonstrated [15]. Moreover, there was an increased incidence of Gram-negative bacterial and fungal infections in a very low birth weight population, and these infants were at significantly increased risk for moderate to severe cerebral palsy and neurodevelopmental impairment at 18 months of age [16].

2.1. Bacterial Pathogens in Neonatal Sepsis

Escherichia coli is one of the main pathogens causing early-onset infections in preterm neonates, accounting for up to 40% of the cases of bacteremia among very low birth weight preterm infants (<1,500 g) [17]. Cerebral white matter injury has been found by MRI following Escherichia coli meningitis in human newborn infants [18]. Furthermore, Escherichia coli induce brain damage in a number of antenatal rabbit and rodent models [19–26]. Also, in a recent study, white matter injury was demonstrated in an animal model of neonatal Escherichia coli sepsis in 5-day-old rat pups [27]. Experimental studies show that early-life Escherichia coli exposure can also have long-term effects, influencing the vulnerability to other factors in adulthood, for example, age-related cognitive decline [28] as well as attenuated glial and cytokine responses to amphetamine challenge [29].

In recent years, coagulase-negative staphylococci (CONS) have emerged as the most prevalent and important neonatal pathogens, responsible for approximately 50% of all episodes of late-onset neonatal sepsis in neonatal intensive care units around the world [30–33]. CONS cause significant morbidity, mortality, and healthcare costs worldwide in preterm newborns, especially in very low birth weight infants [34–38]. The vulnerability of preterm infants to CONS infection has been suggested to be due to the special characteristics of the premature infant’s innate immunity [39]. Although there is no direct evidence of CONS causing perinatal brain injury, the presence of CONS in the chorioamnion space at delivery is associated with increased risk for the development of cerebral palsy in preterm infants [40, 41]. Further, in children with an established diagnosis of cerebral palsy, who are admitted to pediatric intensive care, there is a high rate of carriage of abnormal bacteria, including CONS [42].

In very low birth weight preterm infants with early onset neonatal sepsis, the rate of group B streptococcal (GBS) infections is relatively low in comparison with E. coli infections [17]. There is no direct evidence of GBS sepsis playing a role in cerebral palsy; however, nearly half of all infants who survive an episode of GBS meningitis suffer from long-term neurodevelopmental sequelae [43]. Further, extensive cortical neuronal injury was found in GBS-infected neonatal rats, which was mediated through reactive oxygen intermediates [44, 45].

3. Toll-Like Receptor-Mediated Vulnerability of the Immature Brain

3.1. Toll-Like Receptors

Toll-like receptors (TLRs) play a central role in primary recognition of infectious and viral pathogens. The presence of all 13 known TLRs has been demonstrated in the brain [46–48]. TLR4 mediates cellular activation in response to LPS derived from Escherichia coli [49], while CONS [39] and GBS infections [50] are, at least partly, believed to be mediated by TLR2. Interestingly, the role of TLRs in nonbacterial-induced brain injury has also recently been highlighted [51]. TLRs signal through the recruitment of intracellular adaptor proteins, followed by activation of protein kinases and transcription factors that induce the production of inflammatory mediators (Figure 1). The adaptor protein MyD88 is used by most TLRs, except TLR3, while the TRIF adaptor protein is used only by TLR3 and TLR4. LPS-induced activation of TLR4 elicits, via both MyD88 and TRIF, a broad inflammatory response in tissues, including the immature brain [52].

102153.fig.001
Figure 1: Diagram outlining infectious agents, TLRs, and major signaling pathways. Abbreviations: SE: S. epidermidis; GBS: group B streptococcus; LPT: lipopeptides. LPS: lipopolysaccharide; MyD88: myeloid differentiation primary response gene (88); TRIF: TIR domain-containing adaptor inducing interferon-β-mediated transcription factor; NF-κB: nuclear factor-KappaB; IRF: interferon regulatory factor; IP-10: interferon gamma-induced protein 10; IFN: interferon; TNF: tumor necrosis factor; IL-1: Interleukin -1.
3.2. TLR Expression during Brain Development

There is relatively little information regarding the expression of TLRs in the developing brain. During embryonic life, protein expression of both TLR-3 and -8 has been identified [53, 54], while TLR-2 expression is relatively low before birth and increases during the first two weeks of life [55]. We have shown that mRNA for TLR1-9 is expressed in the neonatal mouse brain [56]. It appears that some of the TLRs may play important roles during normal brain development, as TLR2 inhibits neural progenitor cell proliferation during the embryonic period, and TLR3 deficiency increases proliferation of neural progenitor cells, while TLR8 stimulation inhibits neurite outgrowth [53–55]. In support, TLR2 and TLR4 have been shown to regulate hippocampal neurogenesis in the adult brain [57].

3.3. LPS-Induced Brain Injury

We, and others, have shown that systemic administration of LPS results in brain injury in both fetal and newborn animals [58–60]. These injuries appear, both histologically and by MRI analysis, to be very similar to those found in preterm infants [61]. Furthermore, it is now well established that pre-exposure to LPS can increase the vulnerability of the immature brain to hypoxia-ischemia (HI), in both rats [62, 63] and mice [64]. These effects are TLR4 [65] and MyD88 dependent [64, 66]. In a recent study, it was also shown that a very low dose of LPS, specifically increased the vulnerability of the immature white matter [67]. Low-dose LPS (0.05 mg/kg) sensitized HI injury in P2 rat pups by selectively reducing myelin basic protein expression and the number of oligodendrocytes while increasing neuroinflammation and blood-brain barrier damage in the white matter. The neuroinflammatory responses to LPS/HI appears to be age dependent [68]. Rat pups subjected to LPS/HI at P1 responded with weak cytokine response, while there was a prominent upregulation of cytokines in P12 pups subjected to the same insult. Interestingly, IL-1β was upregulated at both ages; IL-1β injections sensitize the newborn brain to excitotoxicity [69] and repeated IL-1β exposure during the neonatal period induces preterm like brain injury in mice [70].

Although it has clearly been demonstrated that LPS can increase the vulnerability to HI, under certain circumstances LPS can also induce tolerance to brain injury. We have shown that the time interval between LPS exposure and the subsequent HI is imperative to the outcome [71, 72], where a 24 h interval seems to induce a tolerant state that makes the brain less vulnerable. This has been confirmed by others who have implicated several possible mechanisms, including upregulation of corticosterone [73], which is further supported by the fact that administration of dexamethasone prevents learning impairment following LPS/HI in neonatal rats [74]. Furthermore, Akt-mediated eNOS upregulation in neurons and vascular endothelial cells have been implicated in LPS-induced preconditioning [75].

The importance of the time interval between LPS and other insults seems to be a generalized phenomenon. We have recently demonstrated in an in vitro model that conditioned medium from LPS-activated microglia affects the antioxidant Nrf2 system and cell survival in astrocytes in a time-dependent manner. LPS-induced inflammation had dual, time-dependent, effects on the Nrf2 system in that sustained activation (72 h) of GSK3beta and p38 downregulated the Nrf2 system, possibly via the activation of histone deacetylases, changes that were not observed with a 24 h (tolerance) interval [76, 77]. These studies support our previous report demonstrating that reductions in antioxidants were more pronounced when HI was preceded by LPS injection in 8-day rats 3 days prior to the HI insult [78].

3.4. Other TLRs in Perinatal Brain Injury

Compared to TLR4, much less is known about other TLRs in perinatal brain injury. As mentioned above, TLR2, TLR3, and TLR8 can affect normal brain development [53–55]. Activation of TLR2 in neonatal mice decreases volume of cerebral gray matter, white matter in the forebrain, and cerebellar molecular layer [79]. Further, we have recently demonstrated the expression of both TLR1 and TLR2 in the neonatal mouse brain following HI. In these studies, TLR2 deficiency resulted in reduced infarct volume after HI, while TLR-1-deficient mice were not protected [56].

Maternal viral immune activation is believed to increase the risk of psychiatric disorders such as schizophrenia in offspring, and in order to examine this relationship, several authors have investigated the vulnerability of the fetal brain to synthetic double-stranded RNA, polyriboinosinic-polyribocytidilic acid (poly I:C), a TLR3 agonist. Maternal injection with poly I:C towards the end of gestation (≥G15) causes sensorimotor gating deficits in the adult offspring in mice [80] and increased sensitivity to the locomotor-stimulating effects of MK-801 [81]. The effects of Poly I:C appear to be gestational age dependent [82]. Maternal Poly I:C injection on GD9, but not GD17, significantly impaired sensorimotor gating and reduced prefrontal dopamine D1 receptors in adulthood, whereas prenatal immune activation in late gestation impaired working memory, potentiated the locomotor reaction to a NMDA-receptor antagonist, and reduced hippocampal NMDA-receptor subunit 1 expression. In particular, Poly I:C injections early during rodent pregnancy affect structural brain development, such as a transient decrease of myelin basic protein in the neonatal offspring [83] and cerebellar pathology [84].

4. Conclusion

E. coli infections are common in preterm neonates, and considerable evidence suggests that E. coli-induced inflammation play a role in the development of white matter damage in preterm infants. There is much less data available concerning the importance of two other common neonatal pathogens, CONS and GBS, in perinatal brain injury. Furthermore, it is becoming clear that TLRs have important roles during development and may be involved in both pathogen-induced damage as well as so called “sterile” HI-induced inflammation. In order to better understand the underlying causes of perinatal brain injury, the interaction between common neonatal pathogens and TLRs in the newborn brain deserves further investigation.

Acknowledgments

This work was supported by grants from the Swedish Research Council (VR 2009-2630, C. Mallard; VR K2009-54X-21119-01-4, X. Wang), ALFGBG-142881 (C. Mallard), Leducq Foundation (C. Mallard), the European Union (HEALTH-F2-2009-241778, Neurobid, C. Mallard), Åhléns stiftelsen (C. Mallard), Frimurare barnhusfonden (C. Mallard), Lundgrenska stiftelserna (C. Mallard, and X. Wang), and National Natural Science Foundation of China (30973240, X. Wang).

References

  1. N. Marlow, D. Wolke, M. A. Bracewell, and M. Samara, “Neurologic and developmental disability at six years of age after extremely preterm birth,” The New England Journal of Medicine, vol. 352, no. 1, pp. 9–19, 2005. View at Publisher · View at Google Scholar · View at Scopus
  2. O. Dammann and A. Leviton, “Maternal intrauterine infection, cytokines, and brain damage in the preterm newborn,” Pediatric Research, vol. 42, no. 1, pp. 1–8, 1997. View at Google Scholar · View at Scopus
  3. H. Hagberg and C. Mallard, “Effect of inflammation on central nervous system development and vulnerability,” Current Opinion in Neurology, vol. 18, no. 2, pp. 117–123, 2005. View at Google Scholar · View at Scopus
  4. A. Leviton and F. H. Gilles, “An epidemiologic study of perinatal telencephalic leucoencephalopathy in an autopsy population,” Journal of the Neurological Sciences, vol. 18, no. 1, pp. 53–66, 1973. View at Google Scholar · View at Scopus
  5. R. G. Faix and S. M. Donn, “Association of septic shock caused by early-onset group B streptococcal sepsis and periventricular leukomalacia in the preterm infant,” Pediatrics, vol. 76, no. 3, pp. 415–419, 1985. View at Google Scholar · View at Scopus
  6. D. J. Murphy, P. L. Hope, and A. Johnson, “Neonatal risk factors for cerebral palsy in very preterm babies: case-control study,” British Medical Journal, vol. 314, no. 7078, pp. 404–408, 1997. View at Google Scholar · View at Scopus
  7. M. E. Msall, G. M. Buck, B. T. Rogers et al., “Multivariate risks among extremely premature infants,” Journal of Perinatology, vol. 14, no. 1, pp. 41–47, 1994. View at Google Scholar · View at Scopus
  8. M. Wheater and J. M. Rennie, “Perinatal infection is an important risk factor for cerebral palsy in very-low-birthweight infants,” Developmental Medicine and Child Neurology, vol. 42, no. 6, pp. 364–367, 2000. View at Publisher · View at Google Scholar · View at Scopus
  9. D. K. Shah, L. W. Doyle, P. J. Anderson et al., “Adverse neurodevelopment in preterm infants with postnatal sepsis or necrotizing enterocolitis is mediated by white matter abnormalities on magnetic resonance imaging at term,” Journal of Pediatrics, vol. 153, no. 2, pp. 170–175, 2008. View at Publisher · View at Google Scholar · View at Scopus
  10. J. J. Volpe, “Postnatal sepsis, necrotizing entercolitis, and the critical role of systemic inflammation in white matter injury in premature infants,” Journal of Pediatrics, vol. 153, no. 2, pp. 160–163, 2008. View at Publisher · View at Google Scholar · View at Scopus
  11. T. Schmitz, A. Heep, F. Groenendaal et al., “Interleukin-1β, interleukin-18, and interferon-γ expression in the cerebrospinal fluid of premature infants with posthemorrhagic hydrocephalus-markers of white matter damage?” Pediatric Research, vol. 61, no. 6, pp. 722–726, 2007. View at Publisher · View at Google Scholar · View at Scopus
  12. B. J. Stoll, N. I. Hansen, I. Adams-Chapman et al., “Neurodevelopmental and growth impairment among extremely low-birth-weight infants with neonatal infection,” JAMA, vol. 292, no. 19, pp. 2357–2365, 2004. View at Publisher · View at Google Scholar · View at Scopus
  13. C. R. Martin, O. Dammann, E. N. Allred et al., “Neurodevelopment of extremely preterm infants who had necrotizing enterocolitis with or without late bacteremia,” Journal of Pediatrics, vol. 157, no. 5, pp. 751–756, 2010. View at Publisher · View at Google Scholar · View at Scopus
  14. E. M. Graham, C. J. Holcroft, K. K. Rai, P. K. Donohue, and M. C. Allen, “Neonatal cerebral white matter injury in preterm infants is associated with culture positive infections and only rarely with metabolic acidosis,” American Journal of Obstetrics and Gynecology, vol. 191, no. 4, pp. 1305–1310, 2004. View at Publisher · View at Google Scholar · View at Scopus
  15. T. Michael O'Shea, K. L. Klinepeter, P. J. Meis, and R. G. Dillard, “Intrauterine infection and the risk of cerebral palsy in very low-birthweight infants,” Paediatric and Perinatal Epidemiology, vol. 12, no. 1, pp. 72–83, 1998. View at Publisher · View at Google Scholar · View at Scopus
  16. D. K. Benjamin, B. J. Stoll, A. A. Fanaroff et al., “Neonatal candidiasis among extremely low birth weight infants: risk factors, mortality rates, and neurodevelopmental outcomes at 18 to 22 months,” Pediatrics, vol. 117, no. 1, pp. 84–92, 2006. View at Publisher · View at Google Scholar · View at Scopus
  17. B. J. Stoll, N. I. Hansen, R. D. Higgins et al., “Very low birth weight preterm infants with early onset neonatal sepsis: the predominance of Gram-negative infections continues in the National Institute of Child Health and Human Development Neonatal Research Network, 2002–2003,” Pediatric Infectious Disease Journal, vol. 24, no. 7, pp. 635–639, 2005. View at Publisher · View at Google Scholar · View at Scopus
  18. D. K. Shah, A. J. Daley, R. W. Hunt, J. J. Volpe, and T. E. Inder, “Cerebral white matter injury in the newborn following Escherichia coli meningitis,” European Journal of Paediatric Neurology, vol. 9, no. 1, pp. 13–17, 2005. View at Publisher · View at Google Scholar · View at Scopus
  19. S. Kannan, F. Saadani-Makki, O. Muzik et al., “Microglial activation in perinatal rabbit brain induced by intrauterine inflammation: detection with 11C-(R)-PK11195 and small-animal PET,” Journal of Nuclear Medicine, vol. 48, no. 6, pp. 946–954, 2007. View at Publisher · View at Google Scholar · View at Scopus
  20. T. M. Yuan, H. M. Yu, W. Z. Gu, and J. P. Li, “White matter damage and chemokine induction in developing rat brain after intrauterine infection,” Journal of Perinatal Medicine, vol. 33, no. 5, pp. 415–422, 2005. View at Publisher · View at Google Scholar · View at Scopus
  21. T. Debillon, C. Gras-Leguen, S. Leroy, J. Caillon, J. C. Rozé, and P. Gressens, “Patterns of cerebral inflammatory response in a rabbit model of intrauterine infection-mediated brain lesion,” Developmental Brain Research, vol. 145, no. 1, pp. 39–48, 2003. View at Publisher · View at Google Scholar · View at Scopus
  22. J. K. Davies, R. H. Shikes, C. I. Sze et al., “Histologic inflammation in the maternal and fetal compartments in a rabbit model of acute intra-amniotic infection,” American Journal of Obstetrics and Gynecology, vol. 183, no. 5, pp. 1088–1093, 2000. View at Publisher · View at Google Scholar · View at Scopus
  23. Bo Hyun Yoon, Chong Jai Kim, R. Romero et al., “Experimentally induced intrauterine infection causes fetal brain white matter lesions in rabbits,” American Journal of Obstetrics and Gynecology, vol. 177, no. 4, pp. 797–802, 1997. View at Google Scholar · View at Scopus
  24. Y. Pang, S. Rodts-Palenik, Z. Cai, W. A. Bennett, and P. G. Rhodes, “Suppression of glial activation is involved in the protection of IL-10 on maternal E. coli induced neonatal white matter injury,” Developmental Brain Research, vol. 157, no. 2, pp. 141–149, 2005. View at Publisher · View at Google Scholar · View at Scopus
  25. S. Rodts-Palenik, J. Wyatt-Ashmead, Y. Pang et al., “Maternal infection-induced white matter injury is reduced by treatment with interleukin-10,” American Journal of Obstetrics and Gynecology, vol. 191, no. 4, pp. 1387–1392, 2004. View at Publisher · View at Google Scholar · View at Scopus
  26. K. L. Wallace, J. Lopez, J. P. Shaffery, A. Wells, I. A. Paul, and W. A. Bennett, “Interleukin-10/Ceftriaxone prevents E. coli-induced delays in sensorimotor task learning and spatial memory in neonatal and adult Sprague-Dawley rats,” Brain Research Bulletin, vol. 81, no. 1, pp. 141–148, 2010. View at Publisher · View at Google Scholar · View at Scopus
  27. G. Loron, P. Olivier, H. See et al., “Ciprofloxacin prevents myelination delay in neonatal rats subjected to E. coli sepsis,” Annals of Neurology, vol. 69, no. 2, pp. 341–351, 2011. View at Google Scholar
  28. S. D. Bilbo, “Early-life infection is a vulnerability factor for aging-related glial alterations and cognitive decline,” Neurobiology of Learning and Memory, vol. 94, no. 1, pp. 57–64, 2010. View at Publisher · View at Google Scholar · View at Scopus
  29. S. T. Bland, J. T. Beckley, L. R. Watkins, S. F. Maier, and S. D. Bilbo, “Neonatal Escherichia coli infection alters glial, cytokine, and neuronal gene expression in response to acute amphetamine in adolescent rats,” Neuroscience Letters, vol. 474, no. 1, pp. 52–57, 2010. View at Publisher · View at Google Scholar · View at Scopus
  30. B. J. Stoll, N. Hansen, A. A. Fanaroff et al., “Changes in pathogens causing early-onset sepsis in very-low-birth-weight infants,” The New England Journal of Medicine, vol. 347, no. 4, pp. 240–247, 2002. View at Publisher · View at Google Scholar · View at Scopus
  31. B. J. Stoll, N. Hansen, A. A. Fanaroff et al., “Late-onset sepsis in very low birth weight neonates: the experience of the NICHD Neonatal Research Network,” Pediatrics, vol. 110, no. 2, pp. 285–291, 2002. View at Publisher · View at Google Scholar · View at Scopus
  32. M. J. Bizzarro, C. Raskind, R. S. Baltimore, and P. G. Gallagher, “Seventy-five years of neonatal sepsis at Yale: 1928–2003,” Pediatrics, vol. 116, no. 3, pp. 595–602, 2005. View at Publisher · View at Google Scholar · View at Scopus
  33. I. R. Makhoul, P. Sujov, T. Smolkin, A. Lusky, and B. Reichman, “Pathogen-specific early mortality in very low birth weight infants with late-onset sepsis: a national survey,” Clinical Infectious Diseases, vol. 40, no. 2, pp. 218–224, 2005. View at Publisher · View at Google Scholar · View at Scopus
  34. B. J. Stoll and N. Hansen, “Infections in VLBW infants: studies from the NICHD Neonatal Research Network,” Seminars in Perinatology, vol. 27, no. 4, pp. 293–301, 2003. View at Publisher · View at Google Scholar · View at Scopus
  35. C. Vuong and M. Otto, “Staphylococcus epidermidis infections,” Microbes and Infection, vol. 4, no. 4, pp. 481–489, 2002. View at Publisher · View at Google Scholar · View at Scopus
  36. D. Isaacs, “A ten year, multicentre study of coagulase negative staphylococcal infections in Australasian neonatal units,” Archives of Disease in Childhood, vol. 88, no. 2, pp. F89–F93, 2003. View at Google Scholar · View at Scopus
  37. C. M. Healy, K. G. Hulten, D. L. Palazzi, J. R. Campbell, and C. J. Baker, “Emergence of new strains of methicillin-resistant Staphylococcus aureus in a neonatal intensive care unit,” Clinical Infectious Diseases, vol. 39, no. 10, pp. 1460–1466, 2004. View at Publisher · View at Google Scholar · View at Scopus
  38. J. B. López Sastre, D. Coto Cotallo, B. Fernández Colomer et al., “Neonatal sepsis of nosocomial origin: an epidemiological study from the ‘Grupo de Hospitales Castrillo’,” Journal of Perinatal Medicine, vol. 30, no. 2, pp. 149–157, 2002. View at Publisher · View at Google Scholar · View at Scopus
  39. T. Strunk, P. Richmond, K. Simmer, A. Currie, O. Levy, and D. Burgner, “Neonatal immune responses to coagulase-negative staphylococci,” Current Opinion in Infectious Diseases, vol. 20, no. 4, pp. 370–375, 2007. View at Publisher · View at Google Scholar · View at Scopus
  40. R. Mittendorf, R. Covert, J. Kohn, N. Roizen, B. Khoshnood, and K. S. Lee, “The association of coagulase-negative staphylococci isolated from the chorioamnion at delivery and subsequent development of cerebral palsy,” Journal of Perinatology, vol. 21, no. 1, pp. 3–8, 2001. View at Google Scholar · View at Scopus
  41. R. Mittendorf, N. Roizen, A. Moawad, B. Khoshnood, and K. S. Lee, “Association between cerebral palsy and coagulase-negative staphylococci,” The Lancet, vol. 354, no. 9193, pp. 1875–1876, 1999. View at Publisher · View at Google Scholar · View at Scopus
  42. K. Thorburn, M. Jardine, N. Taylor, N. Reilly, R. E. Sarginson, and H. K. F. Van Saene, “Antibiotic-resistant bacteria and infection in children with cerebral palsy requiring mechanical ventilation,” Pediatric Critical Care Medicine, vol. 10, no. 2, pp. 222–226, 2009. View at Publisher · View at Google Scholar · View at Scopus
  43. M. S. Edwards, M. A. Rench, and A. A. M. Haffar, “Long-term sequelae of group B streptococcal meningitis in infants,” Journal of Pediatrics, vol. 106, no. 5, pp. 717–722, 1985. View at Google Scholar · View at Scopus
  44. Y. S. Kim, R. A. Sheldon, B. R. Elliott, Q. Liu, D. M. Ferriero, and M. G. Tauber, “Brain injury in experimental neonatal meningitis due to group B streptococci,” Journal of Neuropathology and Experimental Neurology, vol. 54, no. 4, pp. 531–539, 1995. View at Google Scholar · View at Scopus
  45. S. L. Leib, Y. S. Kim, L. L. Chow, R. A. Sheldon, and M. G. Täuber, “Reactive oxygen intermediates contribute to necrotic and apoptotic neuronal injury in an infant rat model of bacterial meningitis due to group B streptococci,” The Journal of Clinical Investigation, vol. 98, no. 11, pp. 2632–2639, 1996. View at Google Scholar · View at Scopus
  46. M. Bsibsi, R. Ravid, D. Gveric, and J. M. Van Noort, “Broad expression of Toll-like receptors in the human central nervous system,” Journal of Neuropathology and Experimental Neurology, vol. 61, no. 11, pp. 1013–1021, 2002. View at Google Scholar · View at Scopus
  47. B. B. Mishra, U. M. Gundra, and J. M. Teale, “Expression and distribution of Toll-like receptors 11-13 in the brain during murine neurocysticercosis,” Journal of Neuroinflammation, vol. 5, article 53, 2008. View at Publisher · View at Google Scholar · View at Scopus
  48. B. B. Mishra, P. K. Mishra, and J. M. Teale, “Expression and distribution of Toll-like receptors in the brain during murine neurocysticercosis,” Journal of Neuroimmunology, vol. 181, no. 1-2, pp. 46–56, 2006. View at Publisher · View at Google Scholar · View at Scopus
  49. R. I. Tapping, S. Akashi, K. Miyake, P. J. Godowski, and P. S. Tobias, “Toll-like receptor 4, but not Toll-like receptor 2, is a signaling receptor for Escherichia and Salmonella lipopolysaccharides,” Journal of Immunology, vol. 165, no. 10, pp. 5780–5787, 2000. View at Google Scholar · View at Scopus
  50. P. Henneke and R. Berner, “Interaction of neonatal phagocytes with group B streptococcus: recognition and Response,” Infection and Immunity, vol. 74, no. 6, pp. 3085–3095, 2006. View at Publisher · View at Google Scholar · View at Scopus
  51. U. K. Hanisch, T. V. Johnson, and J. Kipnis, “Toll-like receptors: roles in neuroprotection?” Trends in Neurosciences, vol. 31, no. 4, pp. 176–182, 2008. View at Publisher · View at Google Scholar · View at Scopus
  52. S. Eklind, H. Hagberg, X. Wang et al., “Effect of lipopolysaccharide on global gene expression in the immature rat brain,” Pediatric Research, vol. 60, no. 2, pp. 161–168, 2006. View at Publisher · View at Google Scholar · View at Scopus
  53. J. D. Lathia, E. Okun, S. C. Tang et al., “Toll-like receptor 3 is a negative regulator of embryonic neural progenitor cell proliferation,” Journal of Neuroscience, vol. 28, no. 51, pp. 13978–13984, 2008. View at Publisher · View at Google Scholar · View at Scopus
  54. Y. Ma, J. Li, I. Chiu et al., “Toll-like receptor 8 functions as a negative regulator of neurite outgrowth and inducer of neuronal apoptosis,” Journal of Cell Biology, vol. 175, no. 2, pp. 209–215, 2006. View at Publisher · View at Google Scholar · View at Scopus
  55. E. Okun, K. J. Griffioen, T. Gen Son et al., “TLR2 activation inhibits embryonic neural progenitor cell proliferation,” Journal of Neurochemistry, vol. 114, no. 2, pp. 462–474, 2010. View at Publisher · View at Google Scholar · View at Scopus
  56. L. Stridh, P. L.P. Smith, A. S. Naylor, X. Wang, and C. Mallard, “Regulation of Toll-like receptor 1 and -2 in neonatal mice brains after hypoxia-ischemia,” Journal of Neuroinflammation, vol. 8, article 85, 2011. View at Publisher · View at Google Scholar
  57. A. Rolls, R. Shechter, A. London et al., “Toll-like receptors modulate adult hippocampal neurogenesis,” Nature Cell Biology, vol. 9, no. 9, pp. 1081–1088, 2007. View at Publisher · View at Google Scholar · View at Scopus
  58. J. R. Duncan, M. L. Cock, J. P. Y. Scheerlinck et al., “White matter injury after repeated endotoxin exposure in the preterm ovine fetus,” Pediatric Research, vol. 52, no. 6, pp. 941–949, 2002. View at Publisher · View at Google Scholar · View at Scopus
  59. C. Mallard, A. K. Welin, D. Peebles, H. Hagberg, and I. Kjellmer, “White matter injury following systemic endotoxemia or asphyxia in the fetal sheep,” Neurochemical Research, vol. 28, no. 2, pp. 215–223, 2003. View at Publisher · View at Google Scholar · View at Scopus
  60. X. Wang, G. Hellgren, C. Löfqvist et al., “White matter damage after chronic subclinical inflammation in newborn mice,” Journal of Child Neurology, vol. 24, no. 9, pp. 1171–1178, 2009. View at Publisher · View at Google Scholar · View at Scopus
  61. J. Dean, Y. van de Looij, S. V. Sizonenko et al., “Delayed cortical impairment following lipopolysaccharide exposure in preterm fetal sheep,” Annals of Neurology. In press.
  62. S. Eklind, C. Mallard, A. L. Leverin et al., “Bacterial endotoxin sensitizes the immature brain to hypoxic-ischaemic injury,” European Journal of Neuroscience, vol. 13, no. 6, pp. 1101–1106, 2001. View at Publisher · View at Google Scholar · View at Scopus
  63. L. Yang, H. Sameshima, T. Ikeda, and T. Ikenoue, “Lipopolysaccharide administration enhances hypoxic-ischemic brain damage in newborn rats,” Journal of Obstetrics and Gynaecology Research, vol. 30, no. 2, pp. 142–147, 2004. View at Publisher · View at Google Scholar · View at Scopus
  64. X. Wang, L. Stridh, W. Li et al., “Lipopolysaccharide sensitizes neonatal hypoxic-ischemic brain injury in a MyD88-dependent manner,” Journal of Immunology, vol. 183, no. 11, pp. 7471–7477, 2009. View at Publisher · View at Google Scholar · View at Scopus
  65. S. Lehnardt, L. Massillon, P. Follett et al., “Activation of innate immunity in the CNS triggers neurodegeneration through a Toll-like receptor 4-dependent pathway,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 14, pp. 8514–8519, 2003. View at Publisher · View at Google Scholar · View at Scopus
  66. J. M. Dean, X. Wang, A. M. Kaindl et al., “Microglial MyD88 signaling regulates acute neuronal toxicity of LPS-stimulated microglia in vitro,” Brain, Behavior, and Immunity, vol. 24, no. 4, pp. 776–783, 2010. View at Google Scholar
  67. L. W. Wang, Y. C. Chang, C. Y. Lin, J. S. Hong, and C. C. Huang, “Low-dose lipopolysaccharide selectively sensitizes hypoxic ischemia-induced white matter injury in the immature brain,” Pediatric Research, vol. 68, no. 1, pp. 41–47, 2010. View at Publisher · View at Google Scholar · View at Scopus
  68. M.-E. Brochu, S. Girard, K. Lavoie, and G. Sébire, “Developmental regulation of the neuroinflammatory responses to LPS and/or hypoxia-ischemia between preterm and term neonates: an experimental study,” Journal of Neuroinflammation, vol. 8, article 55, 2011. View at Publisher · View at Google Scholar
  69. M. A. Dommergues, J. Patkai, J. C. Renauld, P. Evrard, and P. Gressens, “Proinflammatory cytokines and interleukin-9 exacerbate excitotoxic lesions of the newborn murine neopallium,” Annals of Neurology, vol. 47, no. 1, pp. 54–63, 2000. View at Publisher · View at Google Scholar · View at Scopus
  70. G. Favrais, Y. Van De Looij, B. Fleiss et al., “Systemic inflammation disrupts the developmental program of white matter,” Annals of Neurology. In press. View at Publisher · View at Google Scholar
  71. S. Eklind, C. Mallard, P. Arvidsson, and H. Hagberg, “Lipopolysaccharide induces both a primary and a secondary phase of sensitization in the developing rat brain,” Pediatric Research, vol. 58, no. 1, pp. 112–116, 2005. View at Publisher · View at Google Scholar · View at Scopus
  72. X. Wang, H. Hagberg, C. Nie, C. Zhu, T. Ikeda, and C. Mallard, “Dual role of intrauterine immune challenge on neonatal and adult brain vulnerability to hypoxia-ischemia,” Journal of Neuropathology and Experimental Neurology, vol. 66, no. 6, pp. 552–561, 2007. View at Publisher · View at Google Scholar · View at Scopus
  73. T. Ikeda, L. Yang, T. Ikenoue, C. Mallard, and H. Hagberg, “Endotoxin-induced hypoxic-ischemic tolerance is mediated by up-regulation of corticosterone in neonatal rat,” Pediatric Research, vol. 59, no. 1, pp. 56–60, 2006. View at Publisher · View at Google Scholar · View at Scopus
  74. T. Ikeda, K. Mishima, N. Aoo et al., “Dexamethasone prevents long-lasting learning impairment following a combination of lipopolysaccharide and hypoxia-ischemia in neonatal rats,” American Journal of Obstetrics and Gynecology, vol. 192, no. 3, pp. 719–726, 2005. View at Publisher · View at Google Scholar · View at Scopus
  75. H. Y. Lin, C. L. Wu, and C. C. Huang, “The akt-endothelial nitric oxide synthase pathway in lipopolysaccharide preconditioning-induced hypoxic-ischemic tolerance in the neonatal rat brain,” Stroke, vol. 41, no. 7, pp. 1543–1551, 2010. View at Publisher · View at Google Scholar · View at Scopus
  76. F. Correa, E. Ljunggren, C. Mallard, M. Nilsson, S. G. Weber, and M. Sandberg, “The Nrf2-inducible antioxidant defense in astrocytes can be both up- and down-regulated by activated microglia:Involvement of p38 MAPK,” Glia, vol. 59, no. 5, pp. 785–799, 2011. View at Publisher · View at Google Scholar
  77. F. Correa, C. Mallard, M. Nilsson, and M. Sandberg, “Activated microglia decrease histone acetylation and Nrf2-inducible anti-oxidant defence in astrocytes: restoring effects of inhibitors of HDACs, p38 MAPK and GSK3β,” Neurobiology of Disease, vol. 44, no. 1, pp. 142–151, 2011. View at Publisher · View at Google Scholar
  78. X. Wang, P. Svedin, C. Nie et al., “N-Acetylcysteine reduces lipopolysaccharide-sensitized hypoxic-ischemic brain injury,” Annals of Neurology, vol. 61, no. 3, pp. 263–271, 2007. View at Publisher · View at Google Scholar · View at Scopus
  79. X. Du, B. Fleiss, H. Li et al., “Systemic stimulation of TLR2 impairs neonatal mouse brain development,” PLoS One, vol. 6, no. 5, Article ID e19583, 2011. View at Publisher · View at Google Scholar
  80. L. Shi, S. H. Fatemi, R. W. Sidwell, and P. H. Patterson, “Maternal influenza infection causes marked behavioral and pharmacological changes in the offspring,” Journal of Neuroscience, vol. 23, no. 1, pp. 297–302, 2003. View at Google Scholar · View at Scopus
  81. L. Zuckerman and I. Weiner, “Maternal immune activation leads to behavioral and pharmacological changes in the adult offspring,” Journal of Psychiatric Research, vol. 39, no. 3, pp. 311–323, 2005. View at Publisher · View at Google Scholar · View at Scopus
  82. U. Meyer, M. Nyffeler, B. K. Yee, I. Knuesel, and J. Feldon, “Adult brain and behavioral pathological markers of prenatal immune challenge during early/middle and late fetal development in mice,” Brain, Behavior, and Immunity, vol. 22, no. 4, pp. 469–486, 2008. View at Publisher · View at Google Scholar · View at Scopus
  83. M. Makinodan, K. Tatsumi, T. Manabe et al., “Maternal immune activation in mice delays myelination and axonal development in the hippocampus of the offspring,” Journal of Neuroscience Research, vol. 86, no. 10, pp. 2190–2200, 2008. View at Publisher · View at Google Scholar · View at Scopus
  84. L. Shi, S. E. P. Smith, N. Malkova, D. Tse, Y. Su, and P. H. Patterson, “Activation of the maternal immune system alters cerebellar development in the offspring,” Brain, Behavior, and Immunity, vol. 23, no. 1, pp. 116–123, 2009. View at Publisher · View at Google Scholar · View at Scopus