Single dose of an adenovirus vectored mouse interferon-α protects mice from lethal EV71 challenge.
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 106PFU 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.
Laboratory of Molecular RNA Virology and Antiviral Strategies, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, MD4 Level 5, 5 Science Drive 2, Singapore 117597, Singapore.
Jialei
J
Sun
Defyrus Inc., 2 Bloor Street West, Suite 2602, Toronto, ON, M4W 3E2, Canada.
Jane
J
Ennis
Defyrus Inc., 2 Bloor Street West, Suite 2602, Toronto, ON, M4W 3E2, Canada.
Jeffrey D
JD
Turner
Laboratory of Molecular RNA Virology and Antiviral Strategies, Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, MD4 Level 5, 5 Science Drive 2, Singapore 117597, Singapore. Electronic address: miccjh@nus.edu.sg.
Justin Jang Hann
JJ
Chu
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D000998:Antiviral Agents; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D029821:Enterovirus A, Human / Q000187:drug effects / Q000302:isolation & purification; D004769:Enterovirus Infections / Q000517:prevention & control* / Q000628:therapy / Q000821:virology; D005822:Genetic Vectors; D006232:Hand, Foot and Mouth Disease / Q000517:prevention & control / Q000628:therapy / Q000821:virology; D016898:Interferon-alpha / Q000008:administration & dosage / Q000235:genetics* / Q000627:therapeutic use; D007371:Interferon-gamma / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D016019:Survival Analysis; D019562:Viral Load / Q000187:drug effects
D000998:Antiviral Agents; C554329:Ifna1 protein, mouse; D016898:Interferon-alpha; D007371:Interferon-gamma
DEF201; EV71; Murine model; Prophylactic effects; Therapeutic effects