Neonatal sepsis is one of the most difficult and costly problems to treat and prevent. Despite antimicrobial therapy, 39% of neonates with sepsis die or suffer major chronic morbidity. Investigations of the neonatal-host immune response to sepsis and its impact on poor long-term outcomes have lagged behind older children and adults. During my fellowship training I developed and validated a clinically-relevant neonatal murine model of polymicrobial sepsis to analyze the neonatal-specific immune response to sepsis-causing agents. We found that neonates exhibit an attenuated innate immune response and are more susceptible to sepsis compared to young adults. Specifically, septic murine neonates produced up to 60 times less IL-1? than adults. IL-1? production, critical for innate immune cellular function, is intimately linked to inflammasome function. Therefore, we propose to explore the role of inflammasome signaling during murine neonatal sepsis using transgenic knockout mice lacking key inflammasome components. Next, we will determine the differences between neonates and adults in upstream and downstream inflammasome signaling (inflammasome-specific mRNA expression and protein production) following activation of innate immunity receptors (TLRs). Lastly, we will determine the role of enhanced inflammasome activation (using a genetic knock-in humanized mouse) or administration of its mature (active) products (IL-1?, IL-18) as potential therapies for neonatal sepsis. Cumulatively, we will search for hitherto unknown features of inflammasome development during ontogeny and generate new knowledge about currently poorly understood parameters of the neonatal sepsis through determination of the role of inflammasome signaling. Thus, determining the impact of specific deficiencies in inflammasome components on neonatal vs. adult sepsis and providing direct proof about their potential importance in the susceptibility to and outcome of neonatal sepsis will represent major advance in this research front. Moreover, this investigation will help in the development of much needed biomarkers for neonatal sepsis susceptibility and identification of novel targets for therapy, such as inflammasome gain-offunction immunotherapy directed at improving sepsis outcomes. We will identify the differences in inflammasome signaling intermediates that result in the large discrepancy in IL-1? production between septic neonates and adults. Identification of mechanism(s) behind this large difference will allow development of targeted approaches that may lead to improved outcomes. We will thus explore the potential for translational value of inflammasome activation or for provision of its mature products as novel immunotherapies for neonatal sepsis in the aftermath of the negative outcome of intravenous immunoglobulin therapy for neonatal sepsis in a recent multicenter trial (NEJM 2011). We surmise that our focus on one of the most challenging problems in neonatology is consistent with the NIGMS' strategic mission to develop the foundation for advances in disease diagnosis, treatment and prevention as well as development of the next generation of physician-scientists.

Public Health Relevance

Newborns, particularly those born prematurely, have a very high risk of death or life-long complications due to systemic infections-associated sepsis known also as 'blood poisoning'-despite being treated with antimicrobial drugs. We discovered that a key blood protein interleukin 1?, which is important for defense against infections, is grossly deficient in neonatal sepsis. In this proposal, we will determine the mechanism for this defect and new means to improve diagnosis and treatment of neonatal sepsis.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08GM106143-06
Application #
9240644
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Dunsmore, Sarah
Project Start
2013-04-01
Project End
2018-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
6
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Florida
Department
Pediatrics
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Nielsen, Daniel W; Ricker, Nicole; Barbieri, Nicolle L et al. (2018) Complete Genome Sequence of the Multidrug-Resistant Neonatal Meningitis Escherichia coli Serotype O75:H5:K1 Strain mcjchv-1 (NMEC-O75). Microbiol Resour Announc 7:
Benjamin, John T; Moore, Daniel J; Bennett, Clayton et al. (2018) Cutting Edge: IL-1? and Not IL-1? Drives IL-1R1-Dependent Neonatal Murine Sepsis Lethality. J Immunol 201:2873-2878
Lawrence, Shelley M; Ruoss, Jessica Lauren; Wynn, James L (2018) IL-17 in neonatal health and disease. Am J Reprod Immunol 79:e12800
Raymond, Steven L; Hawkins, Russell B; Murphy, Tyler J et al. (2018) Impact of toll-like receptor 4 stimulation on human neonatal neutrophil spontaneous migration, transcriptomics, and cytokine production. J Mol Med (Berl) 96:673-684
Good, Misty; McElroy, Steven J; Berger, Jennifer N et al. (2018) Limited achievement of NIH research independence by pediatric K award recipients. Pediatr Res 84:479-480
Lawrence, Shelley M; Wynn, James L (2018) Chorioamnionitis, IL-17A, and fetal origins of neurologic disease. Am J Reprod Immunol 79:e12803
Rincon, J C; Cuenca, A L; Raymond, S L et al. (2018) Adjuvant pretreatment with alum protects neonatal mice in sepsis through myeloid cell activation. Clin Exp Immunol 191:268-278
Good, Misty; McElroy, Steven J; Berger, Jennifer N et al. (2018) Name and Characteristics of National Institutes of Health R01-Funded Pediatric Physician-Scientists: Hope and Challenges for the Vanishing Pediatric Physician-Scientists. JAMA Pediatr 172:297-299
Sweeney, Timothy E; Wynn, James L; Cernada, María et al. (2018) Validation of the Sepsis MetaScore for Diagnosis of Neonatal Sepsis. J Pediatric Infect Dis Soc 7:129-135
Collins, Amélie; Weitkamp, Jörn-Hendrik; Wynn, James L (2018) Why are preterm newborns at increased risk of infection? Arch Dis Child Fetal Neonatal Ed 103:F391-F394

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