Project Summary
Neonatal sepsis is a leading cause of death in newly born babies resulting from a bloodstream infection
caused by a variety of bacterial pathogens. Despite increased hygiene practices, LOS incidence has
paradoxically increased in the past forty years due to an increase in cases resulting from commensal species
from the of the normal skin and intestinal flora. Intriguingly, in a substantial portion of LOS, the pathogen can
be found as a resident of the neonatal gut microbial community prior to disease, yet it remains unclear how
bacterial pathogens translocate from the intestine and how the neonatal immune system initially reacts to gut
originating pathogen translocation. In my preliminary studies, I have shown gut residing bacteria can
translocate the epithelium via goblet cells forming goblet cell associated antigen passages (GAPs) and require
CX3CR1 mononuclear phagocytes (MNPs) to gain access to the circulation. Bacterial translocation prior to day
of life 10 is inhibited by maternally supplied proteins in breastmilk. Asynchronous cross-fostering (ACF) of 1
day old pups to dams having delivered a litter 10 days prior results in bacterial translocation between DOL1-
DOL10. Both commensal bacteria and pathogenic clinical sepsis-causing isolates could translocate and gain
systemic access physiologically In ACF mice. However, only mice gavaged with pathogenic E.coli succumbed
to a sepsis-like disease following translocation of pathogenic E.coli, despite similar bacteria burden when
compared to ACF mice with commensal E. coli. ACF mice with pathogenic E.coli, developed an inflammatory
signature in the intestinal lamina propria and had increased systemic IL6, produced by CX3CR1+ MNPs,
suggesting a mechanism to differentially respond to translocation commensals and pathogens by the mucsoal
immune system. It has been assumed the neonatal response is one of immaturity and ignorance that lacks the
ability to properly fight bacterial pathogens due to a state of immunosuppression until the immune system fully
matures. However, my preliminary data indicates a sophisticated innate immune system able to sense distinct
bacterial differences and perceive potential pathogenic threats. My hypothesis based on recent clinical findings
of a cytokine signature unique to neonates including increased serum IL-6 is that this response is initiated by
the MNP cells within the intestine that encounter the translocating bacteria. This project will utilize animal
models, sepsis pathogens, and a variety of flow cytometry-based assays to explore the innate immune
response to sepsis pathogens following translocation from the intestine. Following the completion of this
project, I will understand the innate immune response following pathogen translocation, defining the dynamics
of how CX3CR1 MNPs may contribute to systemic dissemination of bacteria, and how these processes may
differ from the response following commensal translocation. Additionally, this work will allow for the
development of interventions and preventative therapeutics specific for neonatal sepsis cases, by
understanding the unique aspects of the neonatal response to gut originating bacterial pathogens.