RESEARCH ARTICLE Deficiency in Th2 Cytokine Responses Exacerbate Orthopoxvirus Infection

Ectromelia virus (ECTV) causes mousepox in mice, a disease very similar to smallpox in humans. ECTV and variola virus (VARV), the agent of smallpox, are closely related ortho-poxviruses. Mousepox is an excellent small animal model to study the genetic and immuno-logic basis for resistance and susceptibility of humans to smallpox. Resistance to mousepox is dependent on a strong polarized type 1 immune response, associated with ro-bust natural killer (NK) cell, cytotoxic T lymphocyte (CTL) and gamma interferon (IFN-γ) re-sponses. In contrast, ECTV-susceptible mice generate a type 2 response, associated with weak NK cell, CTL and IFN-γ responses but robust IL-4 responses. Nonetheless, suscepti-ble strains infected with mutant ECTV lacking virus-encoded IFN-γ binding protein (vIFN-γbp) (ECTV-IFN-γbpΔ) control virus replication through generation of type 1 response. Since the IL-4/IL-13/STAT-6 signaling pathways polarize type 2/T helper 2 (Th2) responses with a corresponding suppression of IFN-γ production, we investigated whether the com-bined absence of vIFN-γbp, and one or more host genes involved in Th2 response develop-ment, influence generation of protective immunity. Most mutant mouse strains infected wit