Exogenous Interleukin-12 Protects against Lethal Infection with Coxsackievirus B4

ABSTRACT

Infections with the group B coxsackieviruses either can be asymptomatic or can lead to debilitating chronic diseases. To elucidate the mechanism by which these viruses cause chronic disease, we developed a mouse model of chronic pancreatitis by using a virulent variant of coxsackievirus B4, CVB4-V. Infection with CVB4-V results in an early, severe pancreatitis, which can lead to mortality or progress to chronic pancreatitis. Chronic pancreatitis, in this model, is due to immunopathological mechanisms. We investigated whether interleukin-12 (IL-12) could modulate the outcome of CVB4-V infection. Eighty-five percent of the infected mice treated with 500 ng of IL-12 survived, whereas all untreated mice succumbed. To understand the mechanism underlying the beneficial effect of IL-12, we investigated the role of gamma interferon (IFN-γ). Three lines of evidence suggest that the protective effect of IL-12 is due to IFN-γ. First, administration of IL-12 increased the production of endogenous IFN-γ in CVB4-V-infected mice. Both NK and NKT cells were identified as the source of IFN-γ. Second, IFN-γ knockout mice treated with IL-12 succumbed to infection with CVB4-V. Third, wild-type mice treated with IFN-γ survived infection with CVB4-V. Due to the antiviral effects of IFN-γ, we examined whether IL-12 treatment affected viral replication. Administration of IL-12 did not decrease viral replication in the pancreas, but it did prevent extensive tissue damage and the subsequent development of chronic pancreatitis. The data suggest that IL-12 treatment during CVB4-V infection is able to suppress the immunopathological mechanisms that lead to chronic disease.