Central nervous system (CNS) tuberculosis (TB), most often TB meningitis (TBM), is the most severe form of TB and disproportionately affects children, causing death or neurologic disability in over half despite treatment. Current treatment is inadequate ? it is based on pulmonary TB, is not optimized for CNS penetration and does not sufficiently ameliorate the neuroinflammation causing neurologic injury. The K08 award will provide Dr. Tucker, a pediatric intensivist at Johns Hopkins University, the essential time, training, resources and mentorship to achieve her goals. Her long-term goal is to become an independent clinician scientist to better understand the host immune response resulting in brain injury in TBM, to inform antimicrobial and adjunctive therapeutic strategies, and to design therapeutic monitoring tools in order to improve treatment and prognosis of children with this devastating disease. In the current proposal, Dr. Tucker will use a juvenile TBM rabbit model to investigate the following aims: (1) optimize dosing of new TB antimicrobial drugs at the site of infection, (2) determine whether the degree of bacterial burden, inflammation or antimicrobial penetration at the site of infection correlates most with neurologic outcomes using multi-modality position emission tomography (PET) imaging, and (3) determine if adjunctive host-directed, anti-oxidative therapy (dendrimer-N-acetyl-L- cysteine[NAC]) targeted to activated microglia attenuates neuroinflammation and improves neurologic injury. To achieve her long-term goals and complete her K08 aims, Dr. Tucker has assembled an interdisciplinary mentorship team of experienced investigators committed to her success. Her mentors are experts in their fields; Dr. Sujatha Kannan is a Professor of Pediatric Critical Care Medicine, whose research focuses on investigating the role of neuroinflammation in the developing brain and utilization of nanotherapeutics, and Dr. Sanjay Jain is a Professor of Pediatric Infectious Disease and Radiology who is an expert in TBM and development of novel PET imaging tracers. Additionally, her advisory committee strengthens her mentorship with expertise in nanomedicine, mass spectrometry and pharmacometrics to provide a strong foundation for her training. The five- year career development plan will provide training in neuropathology, immunology, pharmacology, metabolomics and biostatistics in order to complete these aims and lead to future R01 applications to investigate therapeutic strategies that will improve the prognosis of children with TBM. Completion of the proposed research will significantly advance our knowledge of the dynamic interactions between bacterial burden, host immune response and antimicrobial penetration at the site of infection and provide new insights into TBM?s pathogenesis. Additionally, this research will provide a foundation for clinical translation to optimize treatment in CNS infections with pharmacokinetic modeling and dendrimer nanodevices to enhance CNS drug delivery as well as novel noninvasive imaging to monitor treatment response. Several novel PET tracers and dendrimer-NAC are already undergoing first-in-human studies or clinical trials which enhances translation to patients.
/RELEVANCE Central nervous system (CNS) tuberculosis (TB) is a chronic CNS infection disproportionately affecting young children and results in high mortality and long-term neurologic sequelae due to ineffective treatment from limited antimicrobial CNS penetration and a poorly understood neuroinflammatory response. This proposal seeks to understand the local pathology within the infected brain to facilitate development of novel host- directed therapy and approaches to improve CNS drug delivery. The overall goal of this research is to optimize treatment strategies in order to decrease secondary brain injury and improve long-term outcomes in children with chronic CNS infections.
