The use of CpG oligodeoxynucleotides as antiviral treatments against Orthopoxvirus infection

Complications with the current smallpox vaccine and the threat of a new smallpox epidemic have dramatically increased efforts to identify new antiviral compounds against orthopoxviruses. CpG oligodeoxynucleotides were investigated here for their ability to confer protection against vaccinia virus (VACV) in a model of orthopoxvirus infection in pre- and post-exposure settings. Intranasal delivery of the B-class CpG 7909, prior to intranasal challenge with VACV, previously resulted in complete protection in a Balb/C mouse model of infection. Immunological analysis found that pre-stimulation with CpG resulted in the local release of pro-inflammatory cytokines such as IFN-a, IFN-y, TNF-a and IL-6 along with chemptactic messengers such as CCL2. In addition, activated innate effector cells such as macrophages, neutrophils, and dendritic cells were identified in high numbers in the lungs of CpG treated mice prior to infection. This heightened immune response persisted throughout early VACV infection in CpG-treated animals compared to that observed in un-stimulated control mice. Mice treated with CpG-B 7909 also initiated a second wave of immune activation late in infection indicative of a more rapidly formed adaptive response. Treatment and infection of B-cell Knock-out (KO) mice and neutrophil ablated mice suggested neither B-cells nor neutrophils alone were crucial in conferring CpGmediated protection against VACV. The success of CpG-B 7909 as a prophylactic against VACV led to its investigation as a post-exposure therapeutic. Intranasal treatment with CpG-BEThOS - Electronic Theses Online ServiceGBUnited Kingdo