Single dose of an adenovirus vectored mouse interferon-α protects mice from lethal EV71 challenge

Abstract

Enterovirus 71 (EV71) causes hand-foot-and-mouth diseases as well as neurological complications in young children. Interferon (IFN) can inhibit the replication of many viruses with low cytotoxic effects. Previously, an adenovirus vectored mouse interferon-α (DEF201), subtype 5, was generated by Wu et al, 2007. In this study, the antiviral effects of DEF201 against EV71 were evaluated in a murine model. 6-day-old BALB/c mice were administered a single dose of DEF201 before or after infection with lethal dose of EV71. The survival rate, clinical symptoms, tissue viral loads and histology pathogenesis were evaluated. IFN gene expression following a single dose of DEF201 maintained high concentrations of 100-9000 pg/mL for more than 7 days in mice serum. Pre-infection administration of a single dose of 10 PFU of DEF201 offered full protection of the mice against EV71 infection compared with the empty Ad5 vector control. In addition, virus load in DEF201-treated mice muscle tissue was significantly decreased as compared with empty vector control. Histopathology analysis revealed that DEF201 significantly prevented the development of severe tissue damage with reduction of viral antigen in the murine muscle tissue. Post-infection treatment at 6 h offered full protection and partial protection at 12 h, indicating that DEF201 could be used as an anti-EV71 therapeutic agent in early stage of EV71 infection. In addition, our study showed that DEF201 enhanced the neutralization ability of serum in EV71-vaccinated mice, implying that DEF201 could promote the production of specific anti-EV71 antibodies. In conclusion, single dose of DEF201 is highly efficacious as a prophylactic agent against EV71 infection in vivo.

Global virus outbreaks: Interferons as 1st responders

“…DEF201, when administered prophylactically 21 days to 24 h prior to CHIKV challenge in mice, reduced CHIKV viral titers [243]. Furthermore, administration of DEF201 at 6 h and 12 h post-lethal EV71 infection of mice resulted in full and partial protection, respectively [241]. Viewed together, these in vivo studies provide a rationale for the evaluation of the prophylactic and therapeutic effects of adenovirus-vectored IFN-α for the treatment of severe acute virus infections when vaccines and/or approved antiviral agents are unavailable.…”

“…CDM-3008 is able to induce JAK-STAT signaling and upregulate ISG expression. Adenovirusvectored IFN-alfacon-1, which has long-lasting antiviral activity, protects mice, hamsters and non-human primates in animal models of enterovirus (EV) 71 [241], EBOV [234,242], Chikungunya virus (CHIKV) [243], and Rift Valley fever virus (RVFV) infection [244]. A single dose of adenovirus-vectored IFN-α (DEF201), given intranasally within 6 h post-RVFV challenge, significantly reduced viral loads in the serum, liver and spleen of hamsters [244].…”

Molecular Pathogenicity of Enteroviruses Causing Neurological Disease

“…Activation of these PRRs initiates a signaling cascade that induces secretion of type I IFNs and stimulates an antiviral environment within the infected and neighboring cells (Müller et al, 1994). The importance of type I IFNs in EV infection was observed when mice pretreated with type I IFN were protected from a fatal infection by EV-A71 and CVA16 Sun et al, 2016). As the immune response contains numerous redundancies to effectively combat pathogens, the virus needs to circumvent these mechanisms to establish an effective CNS infection.…”

Immunocompetent and Immunodeficient Mouse Models for Enterovirus 71 Pathogenesis and Therapy

“…Immunodeficient mice, even without bearing any human receptors for viral entry, can support infection with EV71 clinical isolates, instead of relying on mouse-adapted strains. Innate immunity, such as IFNs, is required for protection from EV71 infection and pathogenesis [71,72]. AG129 mice, which is deficient in both α/β and γ interferon receptors, developed limb paralysis and death, when infected with a non-mouse-adapted EV71 via i.p.…”