PROJECT SUMMARY
Microbial infections are a major cause of infant mortality worldwide. For particularly vulnerable populations
such as pre-term and low birthweight babies, the risk of invasive infections further escalates. The neonatal
period is defined by a distinct, often described as immature, immune system. Many features of a protective
host response to infection are deficient as compared with older children and adults. Our laboratory has
identified that expression of the immune suppressive cytokine interleukin (IL)-27 is elevated in human and
murine neonates. Other recent studies have shown IL-27 to be a biomarker for early onset neonatal sepsis.
This suggests that elevated IL-27 may represent a risk factor and when further increased during bacterial
challenge, compromise the host immune response. The overall premise of the current proposal is that IL-27 is
a host molecule that represents a target for immune intervention to improve the host response and reduce
susceptibility to bacterial infection early in life. We present strong evidence in a mouse model that the absence
of IL-27 signaling translates to increased survival, improved weight gain, and enhanced clearance of bacteria
during neonatal sepsis. To advance our knowledge of how IL-27 regulates the immune response during
neonatal sepsis, we need to identify the complete repertoire of cell types responsible for IL-27 production,
understand how these population may change over the course of infection, and further define their
functionality. We will address this gap in understanding using an IL-27 reporter mouse that expresses a
fluorescent protein under control of the IL-27p28 promoter. Using whole-animal imaging of the reporter mouse
coupled with luminescent bacteria, this will allow us to identify IL-27 producers, sort them for further functional
analysis, and correlate their presence in infected tissues with the bacterial burden. We also seek to understand
cellular signaling pathways required for IL-27-mediated suppressive activity and compromised control of the
bacterial burden. We hypothesize that signal transducer and activator of transcription (Stat)-3 signals
downstream of IL-27 receptor binding to interfere with lysosomal trafficking and acidification. The net result is
compromised bacterial clearance. Lastly, a primary objective is to investigate the outcomes of antagonizing IL-
27 during neonatal sepsis with the aim of establishing an immunotherapeutic approach for an infectious
disease for which we can currently only offer antibiotics and supportive care. Antibiotic resistance confounds
our reliance on this approach. Administration of a neutralizing antibody conjugated to a fluorescent tag will
allow for visualization of tissue penetration in real time and directly correlate the presence of the antagonist
with control of bacterial growth. At the completion of this project, we expect to have performed preclinical
validation of a promising immunotherapeutic approach to improve immunological responses and susceptibility
to infection disease in newborns, as well as provided an enhanced understanding of how IL-27 regulates host
immunity and interactions with bacterial pathogens during neonatal sepsis.