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Published on: July 24, 2016
Genomic Programming of Human Neonatal Dendritic Cells in Congenital Systemic and In Vitro Cytomegalovirus Infection
Widad Dantoft1, Pablo Martínez-Vicente1,2, James Jafali1
1Division of Infection and Pathway Medicine, School of Biomedical Sciences, University of Edinburgh, Edinburgh, United Kingdom.
Insights
Neonatal dendritic cells exhibit robust programming against human cytomegalovirus (HCMV) infection, with subtle temporal differences compared to adults. This suggests a set-point control mechanism, not immaturity, underlies infant resilience to viral infections.
Area of Science:
- Immunology
- Virology
- Neonatal Research
Background:
- Neonates, especially premature infants, are highly susceptible to infections.
- The role of the neonatal immune system in viral infections is not fully understood.
- Human cytomegalovirus (HCMV) is a common congenital infection.
Purpose of the Study:
- To investigate the host protective responses and pathway biology of neonatal immune cells during HCMV infection.
- To compare the immune response of neonatal and adult dendritic cells to HCMV.
- To identify novel host factors involved in neonatal antiviral defense.
Main Methods:
- Unbiased systems analyses of transcriptomic data from neonatal HCMV infection.
- In vitro analysis of transcriptional programming in neonatal dendritic cells upon HCMV exposure.
- Functional siRNA screening of G-protein coupled receptors (GPCRs) for antiviral and proviral roles.
Main Results:
- Neonatal HCMV infection involves a focused IFN regulatory response associated with dendritic cells.
- Neonatal dendritic cells show early IFN-chemokine responses and later plasticity in cell-cycle and lipid metabolism pathways.
- Novel GPCR-dependent antiviral and proviral factors were identified, and neonatal dendritic cell responses were comparable to adult cells, with only subtle temporal delays.
Conclusions:
- Neonatal dendritic cells demonstrate robust and plastic programming against HCMV, challenging the notion of immune immaturity.
- A set-point control mechanism, rather than immaturity, likely explains neonatal susceptibility and resilience to infection.
- Subtle quantitative and temporal differences in neonatal immune responses may contribute to variability in host defense.
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 in vivo and in vitro. In comparison with adults, a minimal number of subtle quantitative and temporal differences may contribute to variability in host susceptibility and resilience, in a context dependent manner.
