Characterization of a novel murine model of central nervous system catheter infec

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DESCRIPTION (provided by applicant): Cerebrospinal fluid (CSF) shunt infections are a frequent and serious complication in the treatment of hydrocephalus in the pediatric population, with a reported incidence of 5-15%1. The most common organisms responsible for these central nervous system (CNS) catheter infections, Staphylococcus epidermidis and Staphylococcus aureus, are both known to form biofilms2,3. These biofilms are organized communities of bacterial cells that aggregate on the catheter surface, enclosed in a self-produced matrix that protects the organisms. The biofilm's ability to evade the host immune response and antimicrobial agents makes it difficult to manage CNS catheter infections non-surgically, such that catheter removal is currently required to effectively treat these infections. While the growth characteristics and other adaptations of the bacteria required for biofilm formation are being extensively investigated by microbiologists, very little is known about the host interaction with the biofilm, particularly with regard to the immune response to catheter biofilm infections. To explore the neuroimmune response to CNS catheter infections, I have developed a novel model of CNS catheter infection in the mouse. This technique results in a consistent catheter-associated infection with S. aureus and ventriculitis, similar to the sequelae seen in humans with ventricular shunt infections. Establishment of this model provides a powerful tool to identify important factors in the host immune response to CNS biofilms through the use of genetically engineered knockout or transgenic mouse strains. The objective of this study is to utilize this model of CNS catheter infection to characterize the host immune response to a CNS biofilm infection with S. aureus by investigating the kinetics of bacterial growth and the host innate immune response in this setting. Understanding the interactions between the neuroimmune system and the biofilms that form on infected catheters will allow us to explore novel management strategies for these infections in future studies. The overall hypothesis of this K08 proposal is that the host innate immune response in the brain is actively attenuated in response to biofilm colonization of a CNS catheter. To test this hypothesis, we will perform experiments outlined in two specific aims. In Aim 1, we will characterize the bacterial growth kinetics and innate immune response in a murine model of CNS catheter infection. In Aim 2, we will define the role of bacterial regulatory factors in the development of CNS catheter infection by using an isogenic mutant S. aureus strain, deficient in sarA expression, which is known to play a role in biofilm formation. Finally, the candidate is a pediatric infectious disease specialist with a long-standing interest in CNS infections and the role of the host response in pediatric infections. She is a well-supported candidate with an avid interest in becoming a physician scientist who will benefit highly from a Clinical Scientist Development Award. PUBLIC HEALTH RELEVANCE: Cerebrospinal fluid shunt infections are a frequent and serious complication in the treatment of hydrocephalus in the pediatric population. In this proposal, we will study the interactions between the immune system and the biofilms that form on these catheters within the central nervous system. These studies will provide valuable information about the immune response to this biofilm infection within the CNS, potentially leading to novel diagnostic and therapeutic tools for use in management of these infections.