Skin inflammation in RelB−/− mice leads to defective immunity and impaired clearance of vaccinia virus

BackgroundAtopic dermatitis (AD) is an inflammatory skin disorder occurring in genetically predisposed individuals with a systemic TH2 bias. Atopic dermatitis patients exposed to the smallpox vaccine, vaccinia virus (VV), occasionally develop eczema vaccinatum (EV), an overwhelming and potentially lethal systemic infection with VV.ObjectiveTo establish a murine model of EV and examine the effects of skin inflammation on VV immunity.MethodsThe skin of RelB−/− mice, like that of chronic AD lesions in humans, exhibits thickening, eosinophilic infiltration, hyperkeratosis, and acanthosis. RelB−/− and wild-type (WT) control mice were infected with VV via skin scarification. Viral spread, cytokine levels, IgG2a responses and VV-specific T cells were measured.ResultsCutaneously VV-infected RelB−/−, but not WT mice, exhibited weight loss, markedly impaired systemic clearance of the virus and increased contiguous propagation from the inoculation site. This was associated with a dramatically impaired generation of IFN-γ–producing CD8+ vaccinia-specific T cells along with decreased secretion of IFN-γ by VV-stimulated splenocytes. The TH2 cytokines—IL-4, IL-5, IL-13, and IL-10—on the other hand, were overproduced. When infected intraperitoneally, RelB−/− mice generated robust T cell responses with good IFN-γ production.ConclusionAllergic inflammation in RelB−/− mice is associated with dysregulated immunity to VV encountered via the skin. We speculate that susceptibility of AD patients to overwhelming vaccinia virus infection is similarly related to ineffective T cell responses.Clinical implicationsThe susceptibility of patients with AD to EV following cutaneous contact with VV is related to ineffective antiviral immune responses.