Vaccinia Virus Infection Attenuates Innate Immune Responses and Antigen Presentation by Epidermal Dendritic Cells

Abstract

Langerhans cells (LCs) are antigen-presenting cells in the skin that play sentinel roles in host immune defense by secreting proinflammatory molecules and activating T cells. Here we studied the interaction of vaccinia virus with XS52 cells, a murine epidermis-derived dendritic cell line that serves as a surrogate model for LCs. We found that vaccinia virus productively infects XS52 cells, yet this infection displays an atypical response to anti-poxvirus agents. Whereas adenosine N1-oxide blocked virus production and viral protein synthesis during a synchronous infection, cytosine arabinoside had no effect at concentrations sufficient to prevent virus replication in BSC40 monkey kidney cells. Poxviruses are dermatotropic DNA viruses that cause human diseases ranging in severity from a mild local skin eruption (molluscum contagiosum) to a catastrophic systemic illness signaled by a generalized pustular rash (smallpox). Poxviruses employ multiple strategies to evade the immune system, including (i) secretion of virus-encoded soluble cytokine receptors or cytokine analogs that act as molecular decoys to block the activity of host cytokines and (ii) elaboration of viral antagonists of the major intracellular signaling pathways that either trigger apoptosis, establish an antiviral state, or activate proinflammatory responses (reviewed in reference 44). Vaccinia virus, the laboratory prototype for the poxvirus family, has a 200-year history of intentional human infection via the skin for the purpose of smallpox prophylaxis. The stigma of successful vaccination is a localized pustular rash that, in uncomplicated cases, heals without either spreading to adjacent areas of skin or triggering serious systemic inflammation. Major complications of vaccination such as eczema vaccinatum are more common in individuals with abnormal skin immunity (50). Life-threatening progressive vaccinia virus occurs in patients with T-cell immunodeficiency (18). Molluscum contagiosum, a normally benign and self-limited skin infection of healthy children, is either more severe or more difficult to eradicate in children with atopic dermatitis and in immunocompromised patients (13,17). These clinical correlations suggest that delineating the biology of natural poxvirus infections and the mechanisms underlying immunization via scarification (and ways to avoid or treat the complications of vaccination) would benefit from a better understanding of the interactions of poxviruses with the skin immune system.Langerhans cells (LCs) are epidermal antigen-presenting dendritic cells (DCs) that play important roles in skin immune responses (3,40). Derived from CD34 ϩ progenitor cells in the bone marrow (28), they establish their residence in the basal and suprabasal layers of the epidermis. Whereas LCs in noninflamed skin are maintained by skin-resident hematopoietic precursors that self-renew in situ, skin injury results in loss of resident LCs and their replacement by circulating monocyte precursors (19,36). LCs in the epidermis are immature, though capa...

Cytokine-armed vaccinia virus infects the mesothelioma tumor microenvironment to overcome immune tolerance and mediate tumor resolution

“…Thus, proteosomal degradation may have prevented HA expression and resolved DC infection. However, in agreement with the earlier reports, DC maturation did not occur after infection by the VV constructs implying reduced antigen-presenting function [46][47][48][49] and indicating a potentially detrimental bystander response after i.t. VV.…”

Differential Induction of Apoptosis, Interferon Signaling, and Phagocytosis in Macrophages Infected with a Panel of Attenuated and Nonattenuated Poxviruses

“…Poxvirus vectors are efficient activators of host immune responses to virally expressed antigens of distinct origin and therefore are being used as potential vaccines for several pathogens and tumors (6,17,37). In the present study, we have characterized the infection of macrophages with different poxvirus vectors to gain a better understanding of how these vectors activate specific immune responses in these APCs.…”

DNA-triggered innate immune responses are propagated by gap junction communication

“…Many viruses prevent infected cells from propagating ''danger signals'' by inhibiting IRF3-mediated production and secretion of antiviral cytokines such as IFN␤ (4,5). In addition to suppressing antiviral signals, dsDNA viruses such as vaccinia virus, also inhibit host proinflammatory signaling by inhibiting the activation of NF B and limiting the secretion of TNF␣ and IL1␤ (26). This work demonstrated that gap junctions enable the rapid local spread of dsDNA-induced IRF3-activating signals from infected cells to their noninfected neighbors, potentially allowing the escape of host danger signals before the virus has time to disable the antiviral program in the infected cell.…”