Sanne Hoeks

Restrained inflammation and neonatal WMI in viral encephalitis 71 5 DISCUSSION Viral encephalitis in neonates is associatedwith increased risk for impaired neurodevelopmental outcome and it was suggested that innate immune responses might be involved in development of white matter injury. 8 Still, the effect of viral infections on the host immunity and its association with cerebral damage is not well investigated. In this pilot study, we demonstrated that neonates are able to generate a substantial systemic immune response upon viral invasion. Different neurotropic viruses elicit a similar pattern of immune-related proteins in plasma of neonates (Fig 2 A ). This study shows that the distribution and location of WMI following neonatal viral encephalitis shows also striking similarities in EV and HPeV (Fig 1) which is moreover corresponding with cerebral damage after other neurotropic viruses as Rotavirus and Chikungunya virus. 24, 25 Despite these similarities in systemic immune responses and in distribution of WMI, long-term neurodevelopmental outcome is variable. In this study, we showed that the concentration of immune-related proteins in blood after EV, HPeV and HSV encephalitis in neonates appears to be inversely correlated to the severity of cerebral injury and long-term neurodevelopmental outcome (Fig 3). We could identify clusters of immune proteins in plasma, which were associated with long term neurodevelopmental outcome and/or abnormalities on cerebral imaging (cUS and/or MRI). These clusters reveal that a low concentration of various immune-related proteins in plasma is associated with severe cerebral injury and a compromised clinical outcome. Our data suggest that impaired immune activation is associated with white matter injury after viral encephalitis in neonates. Immune responses of neonates are often indicated as impaired or immature since neonatal immune responses deviate from infants and adults. However the ex vivo data described in this study indicate that neonates are able to induce potent immune related protein profiles. The neonatal immune system is characterized by the induction of immune regulatory pathways and have unique features to induce immune tolerance. 26-29 On the other hand, they suffer from these intrinsic adaptations dampening their immune responses, as these adaptations make them vulnerable for infections. Preterm infants are affected even more than term born babies as they have a smaller pool of monocytes and neutrophils, they lack maternal antibodies and have a reduced ability to detect viruses and kill pathogens with a lower production of cytokines limiting T cell activation. 30 This might explain why preterm infants with EV and HPeV encephalitis more often suffer from severe white matter injury with cystic evolution, 31 whereas white matter injury after viral CNS infections is not seen in older infants nor in adults. 32 Furthermore, neonates show a fast brain development that continues after birth. Interfering events like infections disturb brain development especially in the last trimester since the growth velocity of the brain volume accelerates after 25 weeks. 33 Therefore preterm born