Well known drawbacks, of the adenovirus vector (AdV) gene therapy system are largely associated with the antiviral inflammatory response of the host. Vector induced inflammation, the transient expression of transgenes due to the generation of cytotoxic T-cells, and the development of adenovirus specific neutralizing antibodies have clearly limited the usefulness of AdV gene transfer applications. Results from our laboratory have identified TNF-alpha as a key antiviral molecule, involved in orchestration of inflammation, the generation of cytotoxic T-cells and production of anti-AdV neutralizing antibodies. The activation of macrophages by AdV, provides the early antiviral response responsible for secretion of TNF-alpha, which contributes to the activation of the immune cascade that currently compromises AdV gene therapy applications. In this proposal, we are hypothesizing that specific ligands present in the vision are stimulating unknown macrophage receptors (such as toll like receptors), resulting in activation of macrophage and induction of anti-AdV immunity. We are proposing to identify the specific AdV ligand-receptor pathways involved in the macrophage activation cascade, and based on our understanding of these pathways, we will generate viral vectors that are less potent at macrophage activation. These studies will provide basic insight into viral vector-host interactions as well as provide strategies to greatly diminish AdV inflammation/immune activation resulting in enhanced success of AdV gene transfer strategies. 1) Identify the signaling molecules that mediate AdV induction of TNF-alpha in macrophages. 2) Identify the adenoviral molecules that trigger TNF-alpha. 3) Design adenovirus vector mutants that do elicit and at the same time interfere with AdV-mediated TNF-alpha induction; and 4) Test the adenovirus vector mutants in gene transfer experiments to the lung.
| Nociari, Marcelo; Ocheretina, Oksana; Murphy, Mary et al. (2009) Adenovirus induction of IRF3 occurs through a binary trigger targeting Jun N-terminal kinase and TBK1 kinase cascades and type I interferon autocrine signaling. J Virol 83:4081-91 |
| Nociari, Marcelo; Ocheretina, Oksana; Schoggins, John W et al. (2007) Sensing infection by adenovirus: Toll-like receptor-independent viral DNA recognition signals activation of the interferon regulatory factor 3 master regulator. J Virol 81:4145-57 |
| Schoggins, John W; Nociari, Marcelo; Philpott, Nicola et al. (2005) Influence of fiber detargeting on adenovirus-mediated innate and adaptive immune activation. J Virol 79:11627-37 |
| Philpott, Nicola J; Nociari, Marcelo; Elkon, Keith B et al. (2004) Adenovirus-induced maturation of dendritic cells through a PI3 kinase-mediated TNF-alpha induction pathway. Proc Natl Acad Sci U S A 101:6200-5 |
