? DESCRIPTION (provided by applicant): Cerebrospinal fluid shunt placement for the treatment of hydrocephalus is one of the most common procedures performed by pediatric neurosurgeons in the United States. Unfortunately, infection is a frequent complication of this procedure, resulting in prolonged antibiotics and removal of the shunt. Infants are known to be at higher risk of shunt infection, particularly with S. epidermidis. Following infection, these children are at increased risk of seizures, decreased intellectual performance, limitations in daily function and long term mortality but the mechanisms responsible for these neurologic changes are not well defined. Our laboratory has developed a novel model of central nervous system (CNS) catheter infection in infant mice, which demonstrates significant diminutions in innate immune cell influx and key pro-inflammatory mediators despite substantial parenchymal bacterial burdens. This suggests that there is a negative regulator that dampens inflammation. Our preliminary studies demonstrate that IL-10 is key in controlling inflammation in this setting, with heightened inflammatory chemokine and cytokine production concomitant with increased innate immune cell influx in IL-10 knockout (KO) pups. Surprisingly, the heightened inflammation observed in IL-10 KO pups is not associated with a decrease in bacterial burdens but rather, an increased seizure incidence and mortality, suggesting that pro- inflammatory responses may not be beneficial in this setting. We also observed IL-10 dependent increases in STAT3 in the CNS of young mice, which may be an important mechanism of neuroprotection in this setting. We will utilize our mouse infection model to investigate the differences in immune responses to S. epidermidis in the CNS of infants in a longitudinal manner. The role of this immune response in shaping the long-term neurologic outcomes that can occur as a consequence of CNS catheter infection has not been previously described. Given the complex interplay between the host and bacteria that occur over time, our proposed in vivo approach will allow us to better define the host factors influencing disease progression which will have important implications for future diagnostic, screening and treatment modalities. The overall hypothesis of this proposal is that immune responses to S. epidermidis CNS catheter infections are attenuated in young hosts as a protective mechanism for the developing brain. The following Specific Aims will be addressed in this proposal: 1) Pro-inflammatory immune responses are attenuated in an age-dependent manner in response to S. epidermidis infection in the CNS; 2) IL-10 plays an important role in immune regulation and neuroprotection in the setting of CNS catheter infection; and 3) STAT3 plays a key role in IL-10-mediated neuroprotection in the young CNS during S. epidermidis catheter infection by attenuating inflammation in surrounding glia. Furthering our understanding of the unique immune responses to CNS catheter infection in young hosts may facilitate the design of novel immunomodulatory adjunctive therapies to minimize the adverse effects associated with inflammation without compromising bacterial clearance.

R01NS092732

2016-03-01

2021-01-31