The Role of Complement in Cerebrospinal Fluid Shunt Infections

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PROJECT SUMMARY Cerebrospinal fluid shunt infections are a frequent and serious complication of the treatment of hydrocephalus, occurring in 5-30% of patients1, 2. These infections are associated with significant long-term neurologic sequelae such as lower IQ, poor school performance and increased risk of seizures 9-13. The mechanisms responsible for the severe neurologic damage associated with shunt infection are unknown. Studies have demonstrated the role of complement in normal neurologic development through developmentally appropriate complement mediated synaptic pruning by microglia 19,20,22. Additional studies have revealed the role of complement in a variety of neurologic disorders and infection supporting a central role for complement in central nervous system homeostasis and pathology24-33. My preliminary studies in an animal model of shunt infection have demonstrated elevated levels of the complement components C3 and C5 in brain tissue at day 5 and 10 when bacterial burdens are low, suggesting complement may mediate the neurologic damage associated with shunt infections. This is further supported by my preliminary data demonstrating that synaptic pruning is less dramatic in C3 knockout mice. The overall objective of this proposal is to understand the role of complement in a murine model of CNS catheter infection, to facilitate the future identification of novel therapeutic targets to limit neurologic damage in pediatric patients. Understanding the mechanisms whereby complement mediates neurologic damage would allow us to take advantage of many complement inhibitors that are being developed for clinical medicine as potential adjuvants to antibiotic therapy to improve long-term patient outcomes 35,36. Our central hypothesis is that complement components induce microglial-mediated synaptic pruning and are responsible for late-stage cerebral edema. To test this hypothesis, we will perform experiments outlined in two specific aims. In Aim 1, we will identify the primary mode of complement pathway activation during CNS S. epidermidis catheter-associated infection and functional importance. In Aim 2, we will define the molecular mechanisms of complement-mediated damage during CNS catheter infection. Finally, the candidate is a pediatric infectious disease specialist with a long-standing experience investigating shunt infections. She is a well-supported candidate with the goal of becoming a physician scientist and would highly benefit from a Clinical Scientist Development Award.