IL-23 Enhances Host Defense against Vaccinia Virus Infection Via a Mechanism Partly Involving IL-17

Abstract

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-γ-deficient mice did not eliminate VV-IL-12, but did eradicate VV-IL-23. These data indicate that IFN-γ 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-γ-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.

Prognostic significance of genetic variants in the IL-23/Th17 pathway for the outcome of T cell-depleted allogeneic stem cell transplantation

“…28 We found that the rs11209026 variant in donor was associated with decreased risk of fungal infections and, IL-23/Th17 genetic variants in transplantation A Carvalho et al in patient, with improved OS, a finding consistent with the protective effects of IL-23 signaling attenuation in experimental aspergillosis. 25 The fact that donor rs11209026 also increased the risk of CMV infection, while consistent with the enhancing role of IL-23 of antiviral immunity, 39 indicates that fungal more than CMV infection may impact on OS in our cohort of patients. Although the variant could arguably influence OS by modifying the incidence of disease relapse or GVHD, a beneficial effect on relapse was only demonstrated in the univariate analysis and no effect on GVHD was found whatsoever.…”

Vaccinia virus inoculation in sites of allergic skin inflammation elicits a vigorous cutaneous IL-17 response

“…with VV expressing IL-17 (VV-IL-17). In one study, VV-IL-17 was more virulent than WT virus (13), while in the other it was less virulent (14). The reason for the discrepancy is not clear.…”

“…IL-17 is expressed in acute skin lesions of patients with AD and in their peripheral blood CD4 ϩ T cells (11,12). There is controversy as to whether IL-17 promotes or attenuates VV infection (13,14).…”

“…IL-17 is expressed in acute skin lesions of patients with AD and in their peripheral blood CD4 ϩ T cells (11,12). There is controversy as to whether IL-17 promotes or attenuates VV infection (13,14).We have previously shown that epicutaneous (EC) sensitization of BALB/c mice with ovalbumin (OVA) results in skin inflammation with similarities to AD skin lesions, characterized by infiltration with CD4 ϩ cells and eosinophils and by increased expression of mRNA for Th2 cytokines and IL-17, but not 16). In this study, we show that inoculation of VV in OVA-sensitized skin results in larger primary lesions, more satellite lesions, and higher viral loads and markedly higher local expression of IL-17 than VV inoculation in saline-exposed skin or skin with Th1-dominant inflammation.…”

A critical role of IL-17 in modulating the B-cell response during H5N1 influenza virus infection

“…8 Previous studies have demonstrated that IL-17 plays a beneficial role in infections by various pathogens, including pulmonary Mycobacterium bovis, Klebsiella pneumonia and vaccinia virus. [9][10][11] The involvement of IL-17 in protection against influenza virus infection has also been indicated. Studies in vivo have demonstrated that IL-17 can protect mice against lethal infection with both A/Puerto Rico/8/ 34 (H1N1) and A/Alaska/6/77 (H3N2) influenza virus, which is accompanied by an enhanced early influx of neutrophils into the lung.…”