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| Status |
Public on Feb 07, 2023 |
| Title |
Interleukin-27-dependent transcriptome signatures regulation of the transcriptome during neonatal sepsis [ATAC-seq] |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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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| Overall design |
Four-day old C57BL/6 pups were sorted into four groups based on IL27RA status (KO or wild type) and based on infection status with Escherichia coli strain O1:K1:H7 infection (with or without infection; 24 hours). For each of the four group, PolyA RNA-seq were performed for spleen tissue and for myeloid cells enriched from the spleen. Additional ATAC-seq assay to measure chromatin accessibility was performed for myeloid cells from each group.
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| Contributor(s) |
Povroznik JM, Akhter H, Vance JK, Annamanedi M, Dziadowicz SA, Wang L, Divens AM, Hu G, Robinson CM |
| Citation(s) |
36891292 |
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| Submission date |
Dec 03, 2022 |
| Last update date |
May 09, 2023 |
| Contact name |
Gangqing Hu |
| E-mail(s) |
michael.hu@hsc.wvu.edu
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| Organization name |
West Virginia University
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| Department |
MicroBiology, Immunology, and Cell Biology
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| Lab |
2072A, HSC North, Floor 2
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| Street address |
64 Medical Center Drive
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| City |
Morgantown |
| State/province |
West Virginia |
| ZIP/Postal code |
26506-9177 |
| Country |
USA |
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| Platforms (1) |
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| Samples (12)
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| GSM6783951 |
GD249 spleen from pups with no E.coli infection and with intact IL27RA, r1 [ATAC-seq] |
| GSM6783952 |
GD250 spleen from pups with no E.coli infection and with intact IL27RA, r2 [ATAC-seq] |
| GSM6783953 |
GD251 spleen from pups with no E.coli infection and with intact IL27RA, r3 [ATAC-seq] |
| GSM6783954 |
GD252 spleen from pups with E.coli infection and intact IL27RA, r1 [ATAC-seq] |
| GSM6783955 |
GD253 spleen from pups with E.coli infection and intact IL27RA, r2 [ATAC-seq] |
| GSM6783956 |
GD254 spleen from pups with E.coli infection and intact IL27RA, r3 [ATAC-seq] |
| GSM6783957 |
GD125 spleen from pups with no E.coli infection and with IL27RA KO, r1 [ATAC-seq] |
| GSM6783958 |
GD126 spleen from pups with no E.coli infection and with IL27RA KO, r2 [ATAC-seq] |
| GSM6783959 |
GD127 spleen from pups with no E.coli infection and with IL27RA KO, r3 [ATAC-seq] |
| GSM6783960 |
GD129 spleen from pups with E.coli infection and with IL27RA KO, r1 [ATAC-seq] |
| GSM6783961 |
GD130 spleen from pups with E.coli infection and with IL27RA KO, r2 [ATAC-seq] |
| GSM6783962 |
GD131 spleen from pups with E.coli infection and with IL27RA KO, r3 [ATAC-seq] |
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| This SubSeries is part of SuperSeries: |
| GSE220050 |
Interleukin-27-dependent transcriptome signatures regulation of the transcriptome during neonatal sepsis |
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| Relations |
| BioProject |
PRJNA908114 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE220049_RAW.tar |
6.9 Mb |
(http)(custom) |
TAR (of NARROWPEAK) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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