TANK-binding kinase 1-dependent or -independent signaling elicits the cell-type-specific innate immune responses induced by the adenovirus vector

Abstract

Adenovirus vectors (Adv) elicit innate immune responses via several pattern-recognition receptors. Although it has been suggested that various Adv-induced mechanisms play important roles in the induction of innate immunity in vitro, the impacts of these mechanisms in vivo remain unclear. Viral nucleic acids elicit innate immune responses through the recognition of cytosolic nucleic acid sensors and transduce intracellular signals to TANK-binding kinase (TBK) 1. In this study, to determine the impacts of viral nucleic acids on innate immune responses in vivo, we administered transgene-expressing Adv to Tbk1-deficient mice. The systemic Adv administration failed to induce type I interferons (type I IFNs) in the spleen, but not the liver, of Tbk1-deficient mice, resulting in the increase of transgene-expressing cells in the spleen, but not the liver. Moreover, Adv failed to induce type I IFNs in the bone-marrow-derived dendritic cells, but not the mouse embryonic fibroblasts, from Tbk1-deficient mice in vitro. These results support the idea that Adv elicit innate immunity in immune cells and non-immune cells in a TBK1-dependent and TBK1-independent manner, respectively.

Probing GATA factor function in mouse Leydig cells via testicular injection of adenoviral vectors

“…The principal shortcoming of adenoviral gene delivery is that it triggers an immune response in the testis and other organs (Blanchard & Boekelheide 1997, Hendrickx et al 2014, Tsuzuki et al 2016). In the liver, where this response has been characterized in detail, adenoviral transduction stimulates a lymphocytic infiltrate that leads to destruction of genetically modified cells and repopulation with hepatocytes lacking the transgene (Yang et al 1994).…”

Innate immunity to adenovirus: lessons from mice

“…One of the best characterized signaling pathways implicated in the cytosolic sensing of HAdv is initiated by the cyclic guanine adenine synthase (cGAS) which is activated upon binding to double-stranded DNA in the cytosol [65]. The critical role of TBK-1 in mediating IFN-I production was confirmed by administering HAdv5 into Tbk1 À/À Tnf À/À mice [69]. In its turn, 2 0 3 0 -cGAMP activates STINGleading to IRF3-dependent production of type I IFN [65,66].…”

“…It is proposed that when HAdv escapes from the endosomes and reaches the cytosol, virus genomic DNA becomes exposed to cytosolic cGAS, which catalyzes synthesis of 2 0 3 0 -cGAMP second messenger molecules. Using this model, it was determined that the transcriptional activation of IFNa and IFN-b in the spleen 3 h after intravenous virus administration was completely eliminated in the absence of TBK1, while IFN-I production in the liver was found to be TBK-1-independent [69]. Upon intravenous administration of HAdv-C5 to mice deficient in either STING (Tmem173 À/À ) or cGAS (Cgas À/À ), the amounts of IFN-b and several inflammatory cytokines and chemokines in the liver were significantly lower compared to the wild-type mice, when analyzed 5 h after the intravenous virus administration [67].…”

Stimulating DDX3 expression by serotonin 5‐HT receptor 7 through phosphorylation of p53 via the AC‐PKA‐ERK signaling pathway

“…Thus, when one DEAD-box protein is damaged, it cannot be replaced by overexpression of another member. [4][5][6] As a member of the DEAD-box family of putative helicases, DDX3 is distinguished by the existence of a conserved Asp-Glu-Ala-Asp motif. 7 The function of DDX3 and its mechanism of action is not well known.…”

“…16 Serotonin receptors are subdivided into seven distinct classes designed as 5-HT 1 to 5-HT 7 . Up to date, five subtypes of 5-HT 1 (5-HT 1A , 5-HT 1B , 5-HT 1D , 5-HT 1E , and 5-HT 1F ), three subtypes of 5-HT 2 (5-HT 2A , 5-HT 2B , and 5-HT 2C ), and two subtypes of 5-HT 5 have been reported. 16 Each 5-HT[R] couples with cyclic adenosine monophosphate (cAMP) production; however, some 5-HTRs use different signaling pathways.…”