IL-12 and IL-18 act in synergy to clear vaccinia virus infection: involvement of innate and adaptive components of the immune system

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Abstract
Development of a protective host response against intracellular pathogens requires innate and cell-mediated immune responses, with cytokines playing an important role in host defences. Different studies in mice have shown that IL-12 can promote protective immunity to a variety of viruses but, during virus infection, little is known about the in vivo function of IL-18 alone or in combination with IL-12. Using recombinant vaccinia viruses (rVVs) expressing IL-12 and IL-18, the antiviral role of both cytokines in mice has been analysed. The specific anti-VV immune response elicited and the persistence of the virus in target tissues were compared in BALB/c mice inoculated with rVVs expressing IL-12 and IL-18 either singly or in combination. Delivery of IL-12 and IL-18 by rVVs in mice induced a significant enhancement in virus clearance from ovaries and spleen, greater than that expected from the sum of action of both cytokines. Virus clearance involved NK and T cells, as demonstrated in mice depleted of NK cells and in immunodeficient SCID animals. Th1 parameters (CD8+ T cell response and IgG2a : IgG1 ratios) were increased in mice inoculated with rVVs expressing both IL-12 and IL-18 as compared to those animals receiving a single cytokine. These findings indicate that when IL-12 and IL-18 are delivered by rVVs, different mechanisms involving both the innate and specific arms of the immune system act as mediators in the synergistic action of IL-12 and IL-18, leading to VV clearance. These results are of interest for the design of prophylactic as well as therapeutic VV-based strategies.