Jessica Snowden, Ph.D. - US grants

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.

Are witnesses who are accurate at identifying a suspect?s face in a lineup consistently accurate at identifying suspects or in saying what happened during a crime? Given that erroneous eyewitness testimony contributes to wrongful convictions and that jurors give great weight to eyewitness testimony, knowing whether witness accuracy is stable would be helpful. Traditional eyewitness research does not answer these questions, as most studies examine eyewitness memory for only a single witnessed event. Thus, this project seeks to investigate: (1) the stability of witness memory performance, both within and across witness tasks (e.g., lineups, witness reports of criminal events, and resistance to misinformation) and (2) the strength of a number of individual difference variables, including personality and cognitive traits, in predicting eyewitness performance.

The project will examine the stability of witness accuracy both within and across witness accuracy tasks (lineup identification accuracy; accurate memory of the events; and resistance to misleading post-event information about the events) for five brief witnessed events across multiple study sessions. The use of repeated witness tasks for five separate witness events will permit a more sensitive, more generalizable measure of witness accuracy than in prior research.

The stability of witness accuracy has important broader impacts for decision makers (e.g., jurors, prosecutors, police officers, etc.) in the criminal justice system in evaluating the probable accuracy of witness statements or conflicting statements of different witnesses, given that real world witnesses need to be accurate in both their identifications and their event reports regarding a crime. Further, the proposed procedure may provide a new paradigm for investigating witness accuracy. The project will also support the training of a graduate student and expose undergraduate research assistants to the research process.

? 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.

Increasing the number of children from rural areas and minority families in clinical research can improve the health of all children by allowing us to better understand disease and treatment in a wider variety of patients. Nebraska is home to over 470,000 children, 27% of whom reside in rural areas. Nebraska also includes a significant and growing minority pediatric population, over 30% of whom live in poverty. These children are often underrepresented in clinical trials. Thanks to the outreach offered by the pediatricians and pediatric specialists at the University of Nebraska Medical Center (UNMC) and the affiliated Children?s Hospital & Medical Center (Children?s), the proposed Nebraska Pediatric Clinical Trials Unit (NPCTU) is well suited to filling this gap in pediatric clinical trials by linking our well-established research infrastructure with our extensive clinical expertise and diverse patient population to create a central home for pediatric clinical research in Nebraska. Our clinical network includes over 30 outreach clinics throughout the state of Nebraska, as well as clinics in South Dakota and Iowa, and over 60 general pediatric and specialty pediatric clinics. The NPCTU partners this clinical network with the robust research infrastructure of UNMC and Children?s, including a Pediatric Research Office that supports more than 180 pediatric research trials and the UNMC Center for Clinical Trials Research. These entities have extensive experience in providing administrative and clinical support for the development of investigator-initiated studies and participation in multi-center, pharmaceutical and NIH/CDC/HRSA sponsored trials. Thus, the affiliation between UNMC and Children?s creates an environment with excellent pediatric research capabilities. This proposal has considerable institutional support and will integrate the extensive research and clinical resources available in Nebraska to build on current strengths to form a unified Nebraska Pediatric Clinical Trials Unit. In keeping with the goals of the Institutional Development Awards Program (IDeA) States Pediatric Clinical Trials Network, our Specific Aims as a participant in this program are two-fold: 1) To establish the NPCTU as the home for pediatric clinical trials in our region by developing a plan for communication with potential investigators and collaborators about trials, training opportunities and resources to support research. This proposal will also support the professional development of the principal investigator and associated faculty, residents and personnel conducting clinical research at UNMC and Children?s, while building on our existing program to conduct clinical trials research for children with a variety of conditions; and 2) To provide the underserved and rural populations of Nebraska and surrounding states access to state-of-the-art clinical trials. Our clinical outreach network with access to a wide variety of underserved populations uniquely positions the NPCTU to contribute to large-scale national pediatric trials.