Bioluminescence imaging reveals a significant role for complement in liver transduction following intravenous delivery of adenovirus.
The effect of complement on transgene expression was evaluated in vivo and in vitro using mice lacking complement components. Complement component 3 (C3) deficient mice (C3-/-) and appropriate wild-type controls were intravenously injected with a replication incompetent, luciferase-expressing normal Ad5 (Ad5Luc1), or fibritin-fiber Ad5 (Ad5FFLuc1). Repeated, noninvasive bioluminescence imaging was conducted over 35 days. Our data show for the first time that C3 facilitates both short- and long-term hepatic expression of luciferase following systemic delivery. C3-/- mice showed significantly less (P < 0.05) luciferase expression in their liver than treatment-matched wild-type mice when 2.3 x 10(9) (Ad5Luc1) and 4.0 x 10(9) (Ad5Luc1 or Ad5FFLuc1) viral particles (v.p.) were infused. The maximal difference in luciferase activity between C3-/- and wild-type mice was 99-fold difference at 3 days for the 2.3 x 10(9) v.p. dose (Ad5Luc1), 35-fold at 13 days for the 4.0 x 10(9) v.p. dose (Ad5Luc1), and 22-fold at 13 days for the 4.0 x 10(9) v.p. dose (Ad5FFLuc1). Preincubation of Ad5Luc1 with wild-type, C1q-/-, or factor B (FB) deficient mouse sera for 5 min significantly (P < 0.05) increased transduction of mouse liver cells, as compared to preincubation with C3-/- sera or PBS. These results suggest the classical or alternate complement pathway enhances Ad5-mediated liver transduction.
Zinn
K R
KR
Department of Medicine, University of Alabama at Birmingham, 35294, USA.
Szalai
A J
AJ
Stargel
A
A
Krasnykh
V
V
Chaudhuri
T R
TR
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D003176:Complement C3 / Q000235:genetics / Q000502:physiology*; D015870:Gene Expression; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000235:genetics; D007275:Injections, Intravenous; D008099:Liver / Q000201:enzymology / Q000276:immunology*; D008156:Luciferases / Q000235:genetics; D008163:Luminescent Measurements; D051379:Mice; D018345:Mice, Knockout; D013997:Time Factors; D014161:Transduction, Genetic / Q000379:methods*; D019076:Transgenes
D003176:Complement C3; D008156:Luciferases