Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Immune Response of Immature Dendritic Cells after Infection with Human Cytomegalovirus Strain TB40E

ABSTRACT: Microarray analysis and quantitative real-time PCR revealed that TB40E infection of DCs led to changes of the gene expression pattern. A variety of pro-inflammatory cytokines and chemokines (CXCL10, CXCL11, CCL5), TLR3 and genes whose products function downstream of the TLR3 signalling pathway (e.g. IFN-alpha, IFN-beta) were significantly upregulated. Three mock transfected DC vs. three TB40 transfected DCs

ORGANISM(S): Homo sapiens

SUBMITTER: Michael Bonin

PROVIDER: E-GEOD-14816 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Toll-like receptor 3 has no critical role during early immune response of human monocyte-derived dendritic cells after infection with the human cytomegalovirus strain TB40E.

Mezger Markus M Bonin Michael M Kessler Tobias T Gebhardt Florian F Einsele Hermann H Loeffler Juergen J

Viral immunology 20091201 6

Toll-like receptors (TLRs) recognize an increasingly broad range of pathogens, thus demonstrating the importance of these pattern-recognition receptors (PRRs) in host defense. Here, the role of TLR3 in the interaction of monocyte-derived dendritic cells (moDCs) with human cytomegalovirus (HCMV) was investigated by using the TB40E strain, which actively replicates in moDCs. Microarray analysis and quantitative real-time PCR revealed that TB40E infection of moDCs led to changes in the gene express ...[more]

PMID: 19951172

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Project description:The dendritic cell (DC) is a master regulator of immune responses. Pathogenic viruses subvert normal immune function in DCs through the expression of immune antagonists. Understanding how these antagonists interact with the host immune system requires knowledge of the underlying genetic regulatory network that operates during an uninhibited antiviral response. In order to isolate and identify this network, we studied DCs infected with Newcastle Disease Virus (NDV), which is able to stimulate innate immunity and DC maturation through activation of RIG-I signaling, but lacks the ability to evade the human interferon response. To analyze this experimental model, we developed a new approach integrating genome-wide expression kinetics and time-dependent promoter analysis. We found that the genetic program underlying the antiviral cell state transition during the first 18-hours post-infection could be explained by a single regulatory network. Gene expression changes were driven by a step-wise multi-factor cascading control mechanism, where the specific transcription factors controlling expression changed over time. Within this network, most individual genes are regulated by multiple factors, indicating robustness against virus-encoded immune evasion genes. In addition to effectively recapitulating current biological knowledge, we predicted, and validated experimentally, antiviral roles for several novel transcription factors. More generally, our results show how a genetic program can be temporally controlled through a single regulatory network to achieve the large-scale genetic reprogramming characteristic of cell state transitions. Total RNA from Monocyte-derived conventional DCs of 2 different donors were infected with Newcastle disease virus (NDV) or as control with allantoic fluid (AF) alon. DC were then harvested at : 0, 1, 2, 6, 10 and 18 hour for control and 1, 2, 4, 6, 8, 10, 12, 14, 16 and 18 hours for NDV infection. Replicates were performed for each of the donors at all timepoints.

Project description:The physiological function of the immune system and the response to therapeutic immunomodulators may be sensitive to combinatorial cytokine micro-environments that shape the responses of specific immune cells. Previous work shows that paracrine cytokines released by virus-infected human dendritic cells (DC) can dictate the maturation state of naM-CM-/ve DCs. To understand the effects of paracrine signaling, we systematically studied the effects of combinations cytokines in this complex mixture in generating an antiviral state. After naM-CM-/ve DCs were exposed to either IFNM-NM-2 or to paracrine signaling released by DCs infected by Newcastle Disease Virus (NDV), microarray analysis revealed a large number of genes that were differently regulated by the DC-secreted paracrine signaling. In order to identify the cytokine mechanisms involved, we identified 20 cytokines secreted by NDV infected DCs for which the corresponding receptor gene is expressed in naM-CM-/ve DCs. By exposing cells to all combinations of 19 cytokines (leave-one-out studies) we identified 5 cytokines (IFNM-NM-2, TNFM-NM-1, IL-1M-oM-^AM-", TNFSF15 and IL28) as candidates for regulating DC maturation markers. Subsequent experiments identified IFNM-NM-2, TNFM-NM-1 and IL1M-oM-^AM-" as the major synergistic contributors to this antiviral state. This finding was supported by infection studies in vitro, by T cell activation studies and by in vivo infection studies in mouse. Combination of cytokines can cause response states in DCs that differ from those achieved by the individual cytokines alone. These results suggest that the cytokine microenvironment may act via a combinatorial code to direct the response state of specific immune cells. Further elucidation of this code may provide insight into responses to infection and neoplasia as well as guide the development of combinatorial cytokine immunomodulation for infectious, autoimmune and immunosurveillance-related diseases. Cells exposed to the supernatant of NDV infected cells were compared to NDV infected cells, IFNM-NM-2 treated cells and naM-CM-/ve dendritic cells after 8 hours.

Dataset Information

Immune Response of Immature Dendritic Cells after Infection with Human Cytomegalovirus Strain TB40E

Publications

Toll-like receptor 3 has no critical role during early immune response of human monocyte-derived dendritic cells after infection with the human cytomegalovirus strain TB40E.

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