IL-1R Type 1–Deficient Mice Demonstrate an Impaired Host Immune Response against Cutaneous Vaccinia Virus Infection

Abstract

The IL-1 superfamily of cytokines and receptors has been studied extensively. However, the specific roles of IL-1 elements in host immunity to cutaneous viral infection remain elusive. In this study, we applied vaccinia virus (VACV) by scarification to IL-1 receptor type 1 knockout mice (IL-1R1−/−) and found that these mice developed markedly larger lesions with higher viral genome copies in skin than wild-type (WT) mice. The phenotype of infected IL-1R1−/− mice was similar to eczema vaccinatum (EV), a severe side effect of VACV vaccination that may develop in humans with atopic dermatitis (AD). Interestingly, the impaired cutaneous response of IL-1R1−/− mice did not reflect a systemic immune deficiency, since immunized IL-1R1−/− mice survived subsequent lethal VACV intranasal challenge, or defects of T cell activation or T cell homing to the site of inoculation. Histologic evaluation revealed that VACV infection and replication after scarification were limited to the epidermal layer of WT mice, whereas lack of IL-1R1 permitted extension of VACV infection into dermal layers of the skin. We explored the etiology of this discrepancy and determined that IL-1R1−/− mice contained significantly more macrophages and monocyte-derived dendritic cells (mo-DC) in the dermis after VACV scarification. These cells were vulnerable to VACV infection and may augment the transmission of virus to adjacent skin, thus leading to larger skin lesions and satellite lesions in IL-1R1−/− mice. These results suggest new therapeutic strategies for treatment of EV and inform assessment of risks in patients receiving IL-1 blocking antibodies for treatment of chronic inflammatory disorders.

Vaccinia Virus Infection Inhibits Skin Dendritic Cell Migration to Draining Lymph Node

“…CD169+ subcapsular sinus (SCS) macrophages are directly exposed to afferent lymph-borne particulates and thus form a strategic line of defense in the dLN against free-flowing viruses, including VACV, preventing their systemic spread (35). Previous studies confirm VACV infection of SCS macrophages (9, 36). In addition, MVA triggers transient inflammasome activation in SCS macrophages that leads to the recruitment of inflammatory cells into the LN (37).…”

A Critical Role of the IL-1β–IL-1R Signaling Pathway in Skin Inflammation and Psoriasis Pathogenesis

“…Furthermore, it implies that resident commensals may provide a protective role in skin infection. Indeed, deficiency of IL-1R leads to severe cutaneous vaccinia virus infection (Tian et al, 2017). This notion is also supported by a recent study showing that an ocular commensal induces IL-17-producing γδ T cells thus protecting against corneal infection (St Leger et al, 2017).…”

Skin Viral Infections: Host Antiviral Innate Immunity and Viral Immune Evasion

“…The group proposed that scarification allowed keratinocytes to actively produce an antiviral state through secretion of chemokines and cytokines ( 44 ). These findings are corroborated by discoveries that TNF-receptor knockout and IL-1 receptor type 1 knockout mice had larger cutaneous lesions and higher viral copies compared to their wild type counterparts ( 45 , 46 ). In vitro , VACV viral infection of epidermal Langerhans cells (LC) and plasmacytoid dendritic cells (pDCs) resulted in inhibition of their ability to elicit cytokine production, including IFN- α and IFN- γ ( 47 , 48 ).…”