Transcription profiling of dendritic cells infected with Newcastle Disease Virus reveals that antiviral response is dictated by a choreographed cascade of transcription factors

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

SUBMITTER: Uri Hershberg 

PROVIDER: E-GEOD-18791 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress