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 . 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 . 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 . infants with sepsis have an increased incidence of cerebral palsy   and white matter abnormalities [ 511 ] . 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 . 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 . 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 . similar findings were noted in a smaller case - control study , where associations between cerebral palsy , clinical chorioamnionitis and sepsis were demonstrated . 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 . 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 ) . cerebral white matter injury has been found by mri following escherichia coli meningitis in human newborn infants . furthermore , escherichia coli induce brain damage in a number of antenatal rabbit and rodent models [ 1926 ] . 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 . 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   as well as attenuated glial and cytokine responses to amphetamine challenge .   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 [ 3033 ] . cons cause significant morbidity , mortality , and healthcare costs worldwide in preterm newborns , especially in very low birth weight infants [ 3438 ] . 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 . 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 .   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 . 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 . further , extensive cortical neuronal injury was found in gbs - infected neonatal rats , which was mediated through reactive oxygen intermediates [ 44 , 45 ] . 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 [ 4648 ] . tlr4 mediates cellular activation in response to lps derived from escherichia coli , while cons   and gbs infections   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 . 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 . 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 . we have shown that mrna for tlr1 - 9 is expressed in the neonatal mouse brain . 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 [ 5355 ] . in support , we , and others , have shown that systemic administration of lps results in brain injury in both fetal and newborn animals [ 5860 ] . these injuries appear , both histologically and by mri analysis , to be very similar to those found in preterm infants . 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 . these effects are tlr4   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 . 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 . 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-1 was upregulated at both ages ; il-1 injections sensitize the newborn brain to excitotoxicity   and repeated il-1 exposure during the neonatal period induces preterm like brain injury in mice . 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 , which is further supported by the fact that administration of dexamethasone prevents learning impairment following lps / hi in neonatal rats . furthermore , akt - mediated enos upregulation in neurons and vascular endothelial cells have been implicated in lps - induced preconditioning . 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 . compared to tlr4 , much less as mentioned above , tlr2 , tlr3 , and tlr8 can affect normal brain development [ 5355 ] . activation of tlr2 in neonatal mice decreases volume of cerebral gray matter , white matter in the forebrain , and cerebellar molecular layer . 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 . 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   and increased sensitivity to the locomotor - stimulating effects of mk-801 . 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   and cerebellar pathology . 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 .