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Adenovirus Vector-Induced Innate Inflammatory Mediators, MAPK Signaling, As Well As Adaptive Immune Responses Are Dependent upon Both TLR2 and TLR9 In Vivo¹

Daniel M. Appledorn^*, Sonika Patial, Aaron McBride^*, Sarah Godbehere^*, Nico Van Rooijen, Narayanan Parameswaran and Andrea Amalfitano^2,*,

^* Department of Microbiology and Molecular Genetics, Department of Pediatrics, and Department of Physiology, Michigan State University, East Lansing, MI 48824; and Department of Molecular Cell Biology, Faculty of Medicine, Vrije Universiteit Medisch Centrum, Vrije Universiteit, Amsterdam, The Netherlands

Adenovirus (Ad) vectors are promising candidates for both gene transfer and vaccine applications. In this study, we investigated the role of TLR2 in innate and adaptive immune responses to Ad and/or the transgene it expresses following systemic injection. We found that Ad directly activates ERK1/2 in vivo, but that initiation of ERK1/2 activation is primarily a MyD88/TLR2-independent, but Kupffer cell-dependent, event. The complexity of Ad-induced innate immune responses was confirmed when we also found that both TLR2 and MyD88 functions are required for the sustained activation of ERK1/2. Although we found that the initial activation of NF-B by Ads is dependent upon MyD88, but independent of TLR2 in (non-Kupffer cells) the liver, TLR2 significantly influenced the Ad-induced late phase NF-B activation. These very rapid responses were positively correlated with subsequent innate immune responses to the Ad vector, as our results confirmed that the induction of several cytokines and chemokines, and the expression of innate immune response genes following Ad injection were TLR2 dependent in vivo. The requirement of TLR2 in Ad-induced innate responses also correlated with significantly altered adaptive immune responses. For example, our results demonstrate that the generation of Ad-neutralizing Abs, and anti-transgene-specific Abs elicited subsequent to Ad vector treatments, are both dependent upon TLR2 functionality. Finally, we found that several Ad-induced innate immune responses are dependent on both TLR2 and TLR9. Therefore, this study confirms that several (but not all) Ad-induced innate and adaptive immune responses are TLR dependent.

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 A.A. was supported by National Institutes of Health Grants RO1DK-069884 and P01 CA078673, as well the Osteopathic Heritage Foundation.

² Address correspondence and reprint requests to Dr. Andrea Amalfitano, Michigan State University, 4194 Biomedical and Physical Sciences Building, East Lansing, MI 48823. E-mail address: amalfit1{at}msu.edu

³ Abbreviations used in this paper: Ad, adenovirus; ODN, oligodeoxynucleotide; IRF, IFN response factor; q, quantitative; KO, knockout; BMDM, bone marrow-derived macrophage; hpi, hours postinfection; MKP, MAPK phosphatase; TRIF, TIR domain-containing adapter inducing IFN-β.