IL-23 enhances host defense against vaccinia virus infection via a mechanism partly involving IL-17.
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-gamma-deficient mice did not eliminate VV-IL-12, but did eradicate VV-IL-23. These data indicate that IFN-gamma 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-gamma-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.
Kohyama
Shunsuke
S
Department of Microbiology, Faculty of Medicine, Saitama Medical University, Saitama, Japan.
Ohno
Satoshi
S
Isoda
Akihiro
A
Moriya
Osamu
O
Belladonna
Maria Laura
ML
Hayashi
Hidenori
H
Iwakura
Yoichiro
Y
Yoshimoto
Takayuki
T
Akatsuka
Toshitaka
T
Matsui
Masanori
M
D000276:Adjuvants, Immunologic / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis; D002460:Cell Line; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D006801:Humans; D007111:Immunity, Cellular / Q000235:genetics; D007113:Immunity, Innate / Q000235:genetics; D020381:Interleukin-17 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D053759:Interleukin-23 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D041681:NIH 3T3 Cells; D014615:Vaccinia / Q000276:immunology / Q000517:prevention & control; D014616:Vaccinia virus / Q000276:immunology*