The maturation of dendritic cells (DCs) in response to a pathogen is essential for effective immune-mediated control of the infection and protection from subsequent re-infections. Pathogenic viruses have developed strategies to evade immune recognition by antagonizing the cellular machinery responsible for effective DC maturation. DCs, on the other hand, utilize multiple complementary systems to ensure complete maturation when encountering pathogens with the ability to bypass DC activation. These complementary mechanisms are primarily represented by type I IFNs which signal for the expression of anti-viral genes and for the complete maturation of DCs. Sendai virus (SeV) strain Cantell (C) efficiently triggers complete DC maturation irrespective of the presence of functional viral antagonists. Our data have demonstrated that SeV-C is detected in DCs by the intracellular helicases RIG-I and MDA5. Differently from other viruses sensed by these helicases, complete DC maturation in response to SeV-C is fast and independent of cytokine feedback. We have identified SeV defective interfering (DI) particles present in the viral stocks as the responsible for the extraordinarily effective induction of DC maturation by SeV-C. The specific signaling pathways responsible for the potent DC response to SeV-C infection, independently of cytokine complementation, are not known. The goal of this proposal is to implement in our laboratory standard methodology to identify the signaling pathways that participate in the direct response to SeV DI particles. We will use these techniques to perform studies to asses the role of the transcription factors IRFs 3 and 7, NF-kB, and AP-1 and their activation pathways in the induction of a fully functional DC maturation program in response to SeV-C independently of type I IFNs. These transcription factors are known to participate in the transcription of relevant DC maturation genes. The results form this investigation will be used as a lead to design future comprehensive studies aimed to characterize the mechanisms responsible for the direct triggering of complete maturation of DCs by SeV DI particles. The characterization of these mechanisms, which likely constitute the main deterrent for non pathogenic viruses, could lead to novel ways of immune stimulation.
Defective interfering (DI) particles provide SeV stocks with a unique stimulus that triggers potent, fast, and complete maturation of dendritic cells (DCs) independently of the cytokine feedback that is needed to complement the response to other viruses. This grant will allow us to implement in our lab the technology necessary to perform initial studies of the cellular machinery responsible for the extraordinary response to SeV DI particles. These studies are crucial for the comprehensive characterization of the DC mechanisms that efficiently respond to virus infection and should provide novel insights for the development of immunostimulatory molecules.
| Zhang, Jingya; Zhang, Yueting; Dutta, Dipankar J et al. (2011) Proapoptotic and antiapoptotic actions of Stat1 versus Stat3 underlie neuroprotective and immunoregulatory functions of IL-11. J Immunol 187:1129-41 |
| Cotter, Christopher R; Kim, Won-keun; Nguyen, Marie L et al. (2011) The virion host shutoff protein of herpes simplex virus 1 blocks the replication-independent activation of NF-ýýB in dendritic cells in the absence of type I interferon signaling. J Virol 85:12662-72 |
