Interleukin-27-dependent transcriptome signatures during neonatal sepsis
Human newborns exhibit increased vulnerability and risk of mortality from infection that is consistent with key differences in the innate and adaptive immune responses relative to those in adult cells. We have previously shown an increase in the immune suppressive cytokine, IL-27, in neonatal cells...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-02-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1124140/full |
| _version_ | 1797902870823043072 |
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| author | Jessica M. Povroznik Jessica M. Povroznik Halima Akhter Jordan K. Vance Madhavi Annamanedi Sebastian A. Dziadowicz Lei Wang Ashley M. Divens Gangqing Hu Cory M. Robinson Cory M. Robinson |
| author_facet | Jessica M. Povroznik Jessica M. Povroznik Halima Akhter Jordan K. Vance Madhavi Annamanedi Sebastian A. Dziadowicz Lei Wang Ashley M. Divens Gangqing Hu Cory M. Robinson Cory M. Robinson |
| author_sort | Jessica M. Povroznik |
| collection | DOAJ |
| description | Human newborns exhibit increased vulnerability and risk of mortality from infection that is consistent with key differences in the innate and adaptive immune responses relative to those in adult cells. We have previously shown an increase in the immune suppressive cytokine, IL-27, in neonatal cells and tissues from mice and humans. In a murine model of neonatal sepsis, mice deficient in IL-27 signaling exhibit reduced mortality, increased weight gain, and better control of bacteria with reduced systemic inflammation. To explore a reprogramming of the host response in the absence of IL-27 signaling, we profiled the transcriptome of the neonatal spleen during Escherichia coli-induced sepsis in wild-type (WT) and IL-27Rα-deficient (KO) mice. We identified 634 genes that were differentially expressed, and those most upregulated in WT mice were associated with inflammation, cytokine signaling, and G protein coupled receptor ligand binding and signaling. These genes failed to increase in the IL-27Rα KO mice. We further isolated an innate myeloid population enriched in macrophages from the spleens of control and infected WT neonates and observed similar changes in gene expression aligned with changes in chromatin accessibility. This supports macrophages as an innate myeloid population contributing to the inflammatory profile in septic WT pups. Collectively, our findings highlight the first report of improved pathogen clearance amidst a less inflammatory environment in IL-27Rα KO. This suggests 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. |
| first_indexed | 2024-04-10T09:24:04Z |
| format | Article |
| id | doaj.art-29e65ece9a644ec48041acb121f74f59 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-10T09:24:04Z |
| publishDate | 2023-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-29e65ece9a644ec48041acb121f74f592023-02-20T07:15:00ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-02-011410.3389/fimmu.2023.11241401124140Interleukin-27-dependent transcriptome signatures during neonatal sepsisJessica M. Povroznik0Jessica M. Povroznik1Halima Akhter2Jordan K. Vance3Madhavi Annamanedi4Sebastian A. Dziadowicz5Lei Wang6Ashley M. Divens7Gangqing Hu8Cory M. Robinson9Cory M. Robinson10Department of Microbiology, Immunology, & Cell Biology, West Virginia University School of Medicine, Morgantown, WV, United StatesVaccine Development Center, West Virginia University Health Sciences Center, Morgantown, WV, United StatesDepartment of Microbiology, Immunology, & Cell Biology, West Virginia University School of Medicine, Morgantown, WV, United StatesDepartment of Microbiology, Immunology, & Cell Biology, West Virginia University School of Medicine, Morgantown, WV, United StatesDepartment of Microbiology, Immunology, & Cell Biology, West Virginia University School of Medicine, Morgantown, WV, United StatesDepartment of Microbiology, Immunology, & Cell Biology, West Virginia University School of Medicine, Morgantown, WV, United StatesDepartment of Microbiology, Immunology, & Cell Biology, West Virginia University School of Medicine, Morgantown, WV, United StatesDepartment of Microbiology, Immunology, & Cell Biology, West Virginia University School of Medicine, Morgantown, WV, United StatesDepartment of Microbiology, Immunology, & Cell Biology, West Virginia University School of Medicine, Morgantown, WV, United StatesDepartment of Microbiology, Immunology, & Cell Biology, West Virginia University School of Medicine, Morgantown, WV, United StatesVaccine Development Center, West Virginia University Health Sciences Center, Morgantown, WV, United StatesHuman newborns exhibit increased vulnerability and risk of mortality from infection that is consistent with key differences in the innate and adaptive immune responses relative to those in adult cells. We have previously shown an increase in the immune suppressive cytokine, IL-27, in neonatal cells and tissues from mice and humans. In a murine model of neonatal sepsis, mice deficient in IL-27 signaling exhibit reduced mortality, increased weight gain, and better control of bacteria with reduced systemic inflammation. To explore a reprogramming of the host response in the absence of IL-27 signaling, we profiled the transcriptome of the neonatal spleen during Escherichia coli-induced sepsis in wild-type (WT) and IL-27Rα-deficient (KO) mice. We identified 634 genes that were differentially expressed, and those most upregulated in WT mice were associated with inflammation, cytokine signaling, and G protein coupled receptor ligand binding and signaling. These genes failed to increase in the IL-27Rα KO mice. We further isolated an innate myeloid population enriched in macrophages from the spleens of control and infected WT neonates and observed similar changes in gene expression aligned with changes in chromatin accessibility. This supports macrophages as an innate myeloid population contributing to the inflammatory profile in septic WT pups. Collectively, our findings highlight the first report of improved pathogen clearance amidst a less inflammatory environment in IL-27Rα KO. This suggests 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.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1124140/fullinterleukin-27neonateinfectionsepsisgram-negativetranscriptome |
| spellingShingle | Jessica M. Povroznik Jessica M. Povroznik Halima Akhter Jordan K. Vance Madhavi Annamanedi Sebastian A. Dziadowicz Lei Wang Ashley M. Divens Gangqing Hu Cory M. Robinson Cory M. Robinson Interleukin-27-dependent transcriptome signatures during neonatal sepsis Frontiers in Immunology interleukin-27 neonate infection sepsis gram-negative transcriptome |
| title | Interleukin-27-dependent transcriptome signatures during neonatal sepsis |
| title_full | Interleukin-27-dependent transcriptome signatures during neonatal sepsis |
| title_fullStr | Interleukin-27-dependent transcriptome signatures during neonatal sepsis |
| title_full_unstemmed | Interleukin-27-dependent transcriptome signatures during neonatal sepsis |
| title_short | Interleukin-27-dependent transcriptome signatures during neonatal sepsis |
| title_sort | interleukin 27 dependent transcriptome signatures during neonatal sepsis |
| topic | interleukin-27 neonate infection sepsis gram-negative transcriptome |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1124140/full |
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