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* Department of Biochemistry and Molecular Biology,
Department of Medicine, and
Department of Physiology and Biophysics, Faculty of Medicine and
Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Alberta, Canada; and
¶ Department of Biochemistry, University of Lausanne, Epalinges, Switzerland
Adenovirus is a nonenveloped dsDNA virus that activates intracellular innate immune pathways. In vivo, adenovirus-immunized mice displayed an enhanced innate immune response and diminished virus-mediated gene delivery following challenge with the adenovirus vector AdLacZ suggesting that antiviral Abs modulate viral interactions with innate immune cells. Under naive serum conditions in vitro, adenovirus binding and internalization in macrophages and the subsequent activation of innate immune mechanisms were inefficient. In contrast to the neutralizing effect observed in nonhematopoietic cells, adenovirus infection in the presence of antiviral Abs significantly increased FcR-dependent viral internalization in macrophages. In direct correlation with the increased viral internalization, antiviral Abs amplified the innate immune response to adenovirus as determined by the expression of NF-
B-dependent genes, type I IFNs, and caspase-dependent IL-1β maturation. Immune serum amplified TLR9-independent type I IFN expression and enhanced NLRP3-dependent IL-1β maturation in response to adenovirus, confirming that antiviral Abs specifically amplify intracellular innate pathways. In the presence of Abs, confocal microscopy demonstrated increased targeting of adenovirus to LAMP1-positive phagolysosomes in macrophages but not epithelial cells. These data show that antiviral Abs subvert natural viral tropism and target the adenovirus to phagolysosomes and the intracellular innate immune system in macrophages. Furthermore, these results illustrate a cross-talk where the adaptive immune system positively regulates the innate immune system and the antiviral state.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Alberta Heritage Foundation for Medical Research, operating and group grants from the Canadian Institutes for Health Research, and infrastructure grants from the Canadian Foundation for Innovation. D.A.M. is the recipient of an Alberta Heritage Foundation for Medical Reasearch Scholar Award. A.K.Z. was the recipient of a Heart and Stroke Foundation of Canada Studentship.
2 Current address: Department of Pharmacology, University of California Los Angeles, Boyer Hall, Room 329, 611 Charles E. Young Drive East, Los Angeles, CA 90095.
3 Current address: Department of Immunology, Moffitt Cancer Center, MRC 2 East, Room 2068, 12902 Magnolia Drive, Tampa, FL 33612-9416.
4 Address correspondence and reprint requests to Dr. Daniel A. Muruve, Department of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, T2N 4N1 Canada. E-mail address: dmuruve{at}ucalgary.ca
5 Abbreviations used in this paper: CAR, Coxsackievirus adenovirus receptor; HS, human serum; MS, mouse serum; HI, heat inactivated; CCB, cytochalasin B; part, particle.
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