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Ectromelia virus (ECTV), a natural mouse pathogen and an orthopoxvirus, has been used to investigate the correlation between polarized type 1 or type 2 immune responses and resistance to disease in poxvirus infections by using well defined resistant and susceptible mouse strains. Our data show that distinct differences exist in the cytokine profiles expressed in resistant and susceptible mice infected with ECTV. Resistant C57BL/6 mice generate a type 1 cytokine response [IFN-gamma, IL-2, and tumor necrosis factor (TNF)], within the first few days of infection, which is associated with strong cytotoxic T lymphocyte response (CTL) and recovery from ECTV infection. Susceptible strains of mice (BALB/c and A/J) on the other hand generate a type 2 cytokine response (IL-4 but little or no IFN-gamma and IL-2), which is associated with a weak or an absent CTL response, resulting in uncontrolled virus replication and death. Although deletion of IL-4 function alone did not change the outcome of infection in susceptible mice, the loss of IFN-gamma function in resistant mice abrogated natural killer (NK) cell and CTL effector functions resulting in fulminant disease and 100% mortality. Therefore, a clear link exists between the early production of specific type 1 cytokines, in particular, IFN-gamma, the nature of the cellular immune response, and disease outcome in this virus model. This finding in the mousepox model raises the possibility that inappropriate cytokine responses may result in increased susceptibility to smallpox in humans.