Project description:Human newborns exhibit increased vulnerability and risk of mortality from infection. Increased susceptibility to infection during the neonatal period reflects key differences in the innate and adaptive immune responses relative to those in adult cells. We have previously shown an increase in the pleiotropic immune suppressive cytokine, IL-27, in macrophages derived from human umbilical cord blood compared with those obtained from adult peripheral blood. Similar findings exist in the neonatal murine system, as well as elevated splenic transcripts and serum levels. Recently, we established a murine model of neonatal sepsis to explore the impact of early life IL-27 levels on the host response to infection. In this model, neonatal mice deficient in IL-27 signaling exhibit reduced mortality, increased weight gain, and better control of the bacterial burden with reduced systemic inflammation. These results suggest that there is a reprogramming of the host response in the presence of IL-27 signaling. To explore this hypothesis, we profiled the neonatal transcriptome of the spleen in the presence or absence of Escherichia coli-induced sepsis in wild-type (WT) and IL-27Rα-deficient mice. The spleen, a known site of infection, exhibits increased IL-27 expression and bacterial burdens in WT pups that were significantly lower in IL-27Rα KO pups during infection. We identified 549 genes that were differentially expressed in WT neonates in response to E. coli infection. The upregulated genes were associated with inflammation, cytokine signaling, and G protein coupled receptor ligand binding and signaling. The expression level of these genes generally failed to increase in IL-27Rα KO mice upon the E. coli infection. We observed similar changes in gene expression, aligned with changes in chromatin accessibility, for macrophages isolated from the spleens of control and infected neonates with or without IL-27Rα KO, supporting macrophages as an innate myeloid population contributing to the inflammatory profile in septic WT pups. Collectively, our findings highlight a less inflammatory environment in KO pups that is not expected given the anti-inflammatory/suppressive activity of IL-27. However, it is consistent with a lower bacterial burden. This suggests that improved bacterial clearance in the absence of IL-27 signaling does not require a heightened inflammatory state, and instead, there is a direct relationship between IL-27 signaling and bacterial killing. An improved response to infection that is not reliant upon heightened levels of inflammation offers new promise to the potential of antagonizing IL-27 as a host-directed therapy for neonates without concern for driving inflammatory responses that are pathological to host tissues.

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Microbiota-derived polyphosphates govern mucosal immunity through multilevel suppression of STAT/IL-27 signaling (multiome)

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