BioProject

Replication-deficient adenovirus (Ad) type 5 capsids induce potent host innate immune responses. More...

Replication-deficient adenovirus (Ad) type 5 capsids induce potent host innate immune responses. One system pivotal in host innate immune defense is the complement system. Intriguingly, excessive or inappropriate complement activation can result in extreme tissue damage and systemic inflammatory responses similar to those noted immediately after high dose systemic Ad vector injections. To determine if the complement system has a significant role in intensifying Ad-associated acute toxicities, we compared complement deficient (C3-knockout (KO)) mice responses to those of wild type (WT) mice following systemic challenge with Ad vectors. We noted not only thrombocytopenia and rapid increases in plasma IL-6, IFN-γ, TNF-α, and IL-12 levels previously reported after high dose Ad injections into WT mice, but also induction of cytokines IL-2, IL-4, IL-5 and IL-10, G-CSF and GM-CSF, and chemokines KC (CXCL1) and MIP-1. This expanded innate response “profile” was significantly blunted in Ad injected C3-KO mice, with a near complete avoidance of thrombocytopenia. Further validation for complement’s critical role in perturbing these innate responses against Ad were noted after comparison of gene specific RNA transcription levels in C3-KO to WT mice livers. Finally, these disparities were not attributed to a diminished ability of the Ad vectors to transduce C3-KO mice hepatocytes. These results suggest that Ad capsid interaction with the mammalian complement system may exacerbate the toxicity of systemic Ad injections, and thus represents a future target for manipulation in efforts to improve the efficacy and safety profile of Ad mediated gene delivery. Keywords: adenovirus, complement system, time course, innate immune response, toxicity Overall design: C57/Bl6 (Wild-type or C3 Knock Outs) were injected with a high dose of a 1st generation LacZ adenovirus (1.5x10E11 particles per mouse) or mock nijected with 200ul of PBS. Virally transduced liver cell transcriptomes were compared to mick injected mice to determine viral gene network induction or repression in vivo. Less...