Single cell transcriptomics reveals cell type specific features of developmentally regulated responses to lipopolysaccharide between birth and 5 years
BackgroundHuman perinatal life is characterized by a period of extraordinary change during which newborns encounter abundant environmental stimuli and exposure to potential pathogens. To meet such challenges, the neonatal immune system is equipped with unique functional characteristics that adapt to...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-10-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1275937/full |
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| author | James F. Read James F. Read Michael Serralha Jesse D. Armitage Jesse D. Armitage Muhammad Munir Iqbal Mark N. Cruickshank Alka Saxena Deborah H. Strickland Deborah H. Strickland Jason Waithman Patrick G. Holt Patrick G. Holt Anthony Bosco Anthony Bosco |
| author_facet | James F. Read James F. Read Michael Serralha Jesse D. Armitage Jesse D. Armitage Muhammad Munir Iqbal Mark N. Cruickshank Alka Saxena Deborah H. Strickland Deborah H. Strickland Jason Waithman Patrick G. Holt Patrick G. Holt Anthony Bosco Anthony Bosco |
| author_sort | James F. Read |
| collection | DOAJ |
| description | BackgroundHuman perinatal life is characterized by a period of extraordinary change during which newborns encounter abundant environmental stimuli and exposure to potential pathogens. To meet such challenges, the neonatal immune system is equipped with unique functional characteristics that adapt to changing conditions as development progresses across the early years of life, but the molecular characteristics of such adaptations remain poorly understood. The application of single cell genomics to birth cohorts provides an opportunity to investigate changes in gene expression programs elicited downstream of innate immune activation across early life at unprecedented resolution.MethodsIn this study, we performed single cell RNA-sequencing of mononuclear cells collected from matched birth cord blood and 5-year peripheral blood samples following stimulation (18hrs) with two well-characterized innate stimuli; lipopolysaccharide (LPS) and Polyinosinic:polycytidylic acid (Poly(I:C)).ResultsWe found that the transcriptional response to LPS was constrained at birth and predominantly partitioned into classical proinflammatory gene upregulation primarily by monocytes and Interferon (IFN)-signaling gene upregulation by lymphocytes. Moreover, these responses featured substantial cell-to-cell communication which appeared markedly strengthened between birth and 5 years. In contrast, stimulation with Poly(I:C) induced a robust IFN-signalling response across all cell types identified at birth and 5 years. Analysis of gene regulatory networks revealed IRF1 and STAT1 were key drivers of the LPS-induced IFN-signaling response in lymphocytes with a potential developmental role for IRF7 regulation.ConclusionAdditionally, we observed distinct activation trajectory endpoints for monocytes derived from LPS-treated cord and 5-year blood, which was not apparent among Poly(I:C)-induced monocytes. Taken together, our findings provide new insight into the gene regulatory landscape of immune cell function between birth and 5 years and point to regulatory mechanisms relevant to future investigation of infection susceptibility in early life. |
| first_indexed | 2024-03-11T18:06:13Z |
| format | Article |
| id | doaj.art-757825dc49e34f18910ecb96025b5e67 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-11T18:06:13Z |
| publishDate | 2023-10-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj.art-757825dc49e34f18910ecb96025b5e672023-10-17T07:15:13ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-10-011410.3389/fimmu.2023.12759371275937Single cell transcriptomics reveals cell type specific features of developmentally regulated responses to lipopolysaccharide between birth and 5 yearsJames F. Read0James F. Read1Michael Serralha2Jesse D. Armitage3Jesse D. Armitage4Muhammad Munir Iqbal5Mark N. Cruickshank6Alka Saxena7Deborah H. Strickland8Deborah H. Strickland9Jason Waithman10Patrick G. Holt11Patrick G. Holt12Anthony Bosco13Anthony Bosco14Asthma and Airway Disease Research Center, University of Arizona, Tucson, AZ, United StatesTelethon Kids Institute, The University of Western Australia, Perth, WA, AustraliaTelethon Kids Institute, The University of Western Australia, Perth, WA, AustraliaTelethon Kids Institute, The University of Western Australia, Perth, WA, AustraliaSchool of Biomedical Sciences, The University of Western Australia, Nedlands, Western Australia, AustraliaGenomics WA, Joint Initiative of Telethon Kids Institute, Harry Perkins Institute of Medical Research and The University of Western Australia, Nedlands, WA, AustraliaSchool of Biomedical Sciences, The University of Western Australia, Nedlands, Western Australia, AustraliaGenomics WA, Joint Initiative of Telethon Kids Institute, Harry Perkins Institute of Medical Research and The University of Western Australia, Nedlands, WA, AustraliaTelethon Kids Institute, The University of Western Australia, Perth, WA, AustraliaUWA Centre for Child Health Research, The University of Western Australia, Nedlands, WA, AustraliaSchool of Biomedical Sciences, The University of Western Australia, Nedlands, Western Australia, AustraliaTelethon Kids Institute, The University of Western Australia, Perth, WA, AustraliaUWA Centre for Child Health Research, The University of Western Australia, Nedlands, WA, AustraliaAsthma and Airway Disease Research Center, University of Arizona, Tucson, AZ, United StatesDepartment of Immunobiology, The University of Arizona College of Medicine, Tucson, AZ, United StatesBackgroundHuman perinatal life is characterized by a period of extraordinary change during which newborns encounter abundant environmental stimuli and exposure to potential pathogens. To meet such challenges, the neonatal immune system is equipped with unique functional characteristics that adapt to changing conditions as development progresses across the early years of life, but the molecular characteristics of such adaptations remain poorly understood. The application of single cell genomics to birth cohorts provides an opportunity to investigate changes in gene expression programs elicited downstream of innate immune activation across early life at unprecedented resolution.MethodsIn this study, we performed single cell RNA-sequencing of mononuclear cells collected from matched birth cord blood and 5-year peripheral blood samples following stimulation (18hrs) with two well-characterized innate stimuli; lipopolysaccharide (LPS) and Polyinosinic:polycytidylic acid (Poly(I:C)).ResultsWe found that the transcriptional response to LPS was constrained at birth and predominantly partitioned into classical proinflammatory gene upregulation primarily by monocytes and Interferon (IFN)-signaling gene upregulation by lymphocytes. Moreover, these responses featured substantial cell-to-cell communication which appeared markedly strengthened between birth and 5 years. In contrast, stimulation with Poly(I:C) induced a robust IFN-signalling response across all cell types identified at birth and 5 years. Analysis of gene regulatory networks revealed IRF1 and STAT1 were key drivers of the LPS-induced IFN-signaling response in lymphocytes with a potential developmental role for IRF7 regulation.ConclusionAdditionally, we observed distinct activation trajectory endpoints for monocytes derived from LPS-treated cord and 5-year blood, which was not apparent among Poly(I:C)-induced monocytes. Taken together, our findings provide new insight into the gene regulatory landscape of immune cell function between birth and 5 years and point to regulatory mechanisms relevant to future investigation of infection susceptibility in early life.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1275937/fullsingle cell genomicsscRNA-Seqtoll-like receptorslipopolysaccharidepoly(I:C)interferon |
| spellingShingle | James F. Read James F. Read Michael Serralha Jesse D. Armitage Jesse D. Armitage Muhammad Munir Iqbal Mark N. Cruickshank Alka Saxena Deborah H. Strickland Deborah H. Strickland Jason Waithman Patrick G. Holt Patrick G. Holt Anthony Bosco Anthony Bosco Single cell transcriptomics reveals cell type specific features of developmentally regulated responses to lipopolysaccharide between birth and 5 years Frontiers in Immunology single cell genomics scRNA-Seq toll-like receptors lipopolysaccharide poly(I:C) interferon |
| title | Single cell transcriptomics reveals cell type specific features of developmentally regulated responses to lipopolysaccharide between birth and 5 years |
| title_full | Single cell transcriptomics reveals cell type specific features of developmentally regulated responses to lipopolysaccharide between birth and 5 years |
| title_fullStr | Single cell transcriptomics reveals cell type specific features of developmentally regulated responses to lipopolysaccharide between birth and 5 years |
| title_full_unstemmed | Single cell transcriptomics reveals cell type specific features of developmentally regulated responses to lipopolysaccharide between birth and 5 years |
| title_short | Single cell transcriptomics reveals cell type specific features of developmentally regulated responses to lipopolysaccharide between birth and 5 years |
| title_sort | single cell transcriptomics reveals cell type specific features of developmentally regulated responses to lipopolysaccharide between birth and 5 years |
| topic | single cell genomics scRNA-Seq toll-like receptors lipopolysaccharide poly(I:C) interferon |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1275937/full |
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