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IL-23 Enhances Host Defense against Vaccinia Virus Infection Via a Mechanism Partly Involving IL-17¹

Shunsuke Kohyama^*,, Satoshi Ohno^*,, Akihiro Isoda^*,, Osamu Moriya^*, Maria Laura Belladonna, Hidenori Hayashi, Yoichiro Iwakura, Takayuki Yoshimoto^¶, Toshitaka Akatsuka^* and Masanori Matsui^2,*

^* Department of Microbiology, Faculty of Medicine, Saitama Medical University, and Department of Pathological Biochemistry, Faculty of Pharmaceutical Sciences, Josai University, Saitama, Japan; Department of Experimental Medicine, University of Perugia, Perugia, Italy; Center for Experimental Medicine, Institute of Medical Science, University of Tokyo, and ^¶ Intractable Immune System Disease Research Center, Tokyo Medical University, Tokyo, Japan

To investigate roles of IL-23 in viral infection, we have engineered recombinant vaccinia virus (VV) expressing IL-12 (VV-IL-12) and expressing IL-23 (VV-IL-23). We found VV-IL-23 was less virulent in BALB/c mice than wild-type VV (VV-WT), indicating that IL-23 enhances resistance to VV. VV-specific CTL activity in VV-IL-23-infected mice was slightly higher than activity in VV-WT-inoculated mice, although antiviral Ab production and NK activity were not increased. IL-12/23p40-deficient mice survived the infection with VV-IL-23, indicating that IL-23 promotes VV resistance independently of IL-12. The mechanism of the IL-23-mediated resistance was distinct from that of the IL-12-regulated resistance because IFN--deficient mice did not eliminate VV-IL-12, but did eradicate VV-IL-23. These data indicate that IFN- is essential for the IL-12-mediated resistance, but dispensable for the IL-23-regulated resistance. Because IL-17 is a key in the IL-23-regulated resistance to bacteria, we hypothesized an involvement of IL-17 in the resistance to VV. Treatment with an anti-IL-17 mAb resulted in a significant increase of viral titers in VV-IL-23-infected IFN--deficient mice. In addition, VV-IL-17 was less virulent than VV-WT in BALB/c mice, and IL-17-deficient mice were more sensitive to VV-WT than control mice. However, the effect of neutralization with an anti-IL-17 mAb was limited, and IL-17-deficient mice survived the infection with VV-IL-23. Taken together, these data suggest that the IL-23/IL-17 axis plays a certain but subdominant role in the IL-23-mediated resistance to VV. Unveiling of an alternative pathway in the IL-23-regulated resistance might provide a novel strategy against infectious pathogens without side effects of autoimmunity.

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 grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

² Address correspondence and reprint requests to Dr. Masanori Matsui, Department of Microbiology, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-Cho, Iruma-Gun, Saitama 350-0495, Japan. E-mail address: mmatsui{at}saitama-med.ac.jp

³ Abbreviations used in this paper: EAE, experimental allergic encephalomyelitis; VV, vaccinia virus; VV-IL-12, VV expressing IL-12; VV-IL-23, VV expressing IL-23; VV-IL-17, VV expressing IL-17; VV-WT, wild-type VV; sc, single chain; KO, knockout; MOI, multiplicity of infection.