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Dantoft W, Martínez-Vicente P, Jafali J, et al. Genomic Programming of Human Neonatal Dendritic Cells in Congenital Systemic and . Front Immunol. 2017;8:1146doi: 10.3389/fimmu.2017.01146.
Dantoft, W., Martínez-Vicente, P., Jafali, J., Pérez-Martínez, L., Martin, K., Kotzamanis, K., Craigon, M., Auer, M., Young, N. T., Walsh, P., Marchant, A., Angulo, A., Forster, T., & Ghazal, P. (2017). Genomic Programming of Human Neonatal Dendritic Cells in Congenital Systemic and . Frontiers in immunology, 81146. https://doi.org/10.3389/fimmu.2017.01146
Dantoft, Widad, et al. "Genomic Programming of Human Neonatal Dendritic Cells in Congenital Systemic and ." Frontiers in immunology vol. 8 (2017): 1146. doi: https://doi.org/10.3389/fimmu.2017.01146
Dantoft W, Martínez-Vicente P, Jafali J, Pérez-Martínez L, Martin K, Kotzamanis K, Craigon M, Auer M, Young NT, Walsh P, Marchant A, Angulo A, Forster T, Ghazal P. Genomic Programming of Human Neonatal Dendritic Cells in Congenital Systemic and . Front Immunol. 2017 Sep 25;8:1146. doi: 10.3389/fimmu.2017.01146. eCollection 2017. PMID: 28993767; PMCID: PMC5622154.
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Front Immunol. 2017 Sep 25;8:1146. doi: 10.3389/fimmu.2017.01146. eCollection 2017.

Genomic Programming of Human Neonatal Dendritic Cells in Congenital Systemic and .

Frontiers in immunology

Widad Dantoft, Pablo Martínez-Vicente, James Jafali, Lara Pérez-Martínez, Kim Martin, Konstantinos Kotzamanis, Marie Craigon, Manfred Auer, Neil T Young, Paul Walsh, Arnaud Marchant, Ana Angulo, Thorsten Forster, Peter Ghazal

Affiliations

  1. Division of Infection and Pathway Medicine, School of Biomedical Sciences, University of Edinburgh, Edinburgh, United Kingdom.
  2. Immunology Unit, Department of Biomedical Sciences, Medical School, University of Barcelona, Barcelona, Spain.
  3. Quantitative Proteomics, Institute of Molecular Biology, Mainz, Germany.
  4. Synexa Life Sciences, Cape Town, South Africa.
  5. SynthSys-Centre for Synthetic and Systems Biology, School of Engineering, University of Edinburgh, Edinburgh, United Kingdom.
  6. Division of Applied Medicine, Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom.
  7. NSilico Life Science and Department of Computing, Institute of Technology, Cork, Ireland.
  8. Institute for Medical Immunology, Université Libre de Bruxelles, Charleroi, Belgium.

PMID: 28993767 PMCID: PMC5622154 DOI: 10.3389/fimmu.2017.01146

Abstract

Neonates and especially premature infants are highly susceptible to infection but still can have a remarkable resilience that is poorly understood. The view that neonates have an incomplete or deficient immune system is changing. Human neonatal studies are challenging, and elucidating host protective responses and underlying cognate pathway biology, in the context of viral infection in early life, remains to be fully explored. In both resource rich and poor settings, human cytomegalovirus (HCMV) is the most common cause of congenital infection. By using unbiased systems analyses of transcriptomic resources for HCMV neonatal infection, we find the systemic response of a preterm congenital HCMV infection, involves a focused IFN regulatory response associated with dendritic cells. Further analysis of transcriptional-programming of neonatal dendritic cells in response to HCMV infection in culture revealed an early dominant IFN-chemokine regulatory subnetworks, and at later times the plasticity of pathways implicated in cell-cycle control and lipid metabolism. Further, we identify previously unknown suppressed networks associated with infection, including a select group of GPCRs. Functional siRNA viral growth screen targeting 516-GPCRs and subsequent validation identified novel GPCR-dependent antiviral (ADORA1) and proviral (GPR146, RGS16, PTAFR, SCTR, GPR84, GPR85, NMUR2, FZ10, RDS, CCL17, and SORT1) roles. By contrast a gene family cluster of protocadherins is significantly differentially induced in neonatal cells, suggestive of possible immunomodulatory roles. Unexpectedly, programming responses of adult and neonatal dendritic cells, upon HCMV infection, demonstrated comparable quantitative and qualitative responses showing that functionally, neonatal dendritic cell are not overly compromised. However, a delay in responses of neonatal cells for IFN subnetworks in comparison with adult-derived cells are notable, suggestive of subtle plasticity differences. These findings support a set-point control mechanism rather than immaturity for explaining not only neonatal susceptibility but also resilience to infection. In summary, our findings show that neonatal HCMV infection leads to a highly plastic and functional robust programming of dendritic cells

Keywords: congenital abnormalities; homeostasis; immunity; infection; set-point; systems biology; transcriptomics; virus

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