CpG oligodeoxynucleotides and pan-serotype inhibitors control neurotropic dengue infection in novel immune competent neonatal mouse model.

Abstract

Dengue virus (DENV) is a growing global public health threat. The lack of symptomatic immune-competent animal models for dengue has hindered the screening and development of effective therapeutics that can be used to control dengue virus replication and thereby control the progression to severe dengue disease. To address this, we established an infection model in neonatal C57BL/6 mice and showed that a systemic Dengue challenge leads to ataxia, seizures, paralysis, and death within 15 days. The virus was found predominantly in the eye and brain where DENV infects neurons but not astrocytes and causes extensive infiltration of macrophages and microglia activation. The response to infection included upregulation of multiple genes linked to interferons (Ifna, Ifnb, Ifng, Irf7, Irf8, Mx1, Stat1 and Bst2), inflammation (Il6,Tnfa), complement (Cfb,C1ra,C2, C3), cytolysis (Gzma, Gzmb, Prf1) consistent with antiviral responses and inflammation together with neuroprotective regulatory signals (Il27, Il10, and stat2). The increased proinflammatory signature was associated with downregulation neurodevelopmental genes (Calb2, Pvalb, Olig1 and Olig2). We tested the utility of this mouse model by assessing the protection conferred by direct antivirals JNJ-A07 and ST-148 and host-directed antiviral immunomodulatory CpG oligodeoxynucleotide (ODN), alone or in combination against lethal dengue viral infection. The data showed that immunomodulatory CpG ODN and antiviral JNJ-A07 improved the survival of neonatal mice, and protection from lethal neurotropic infection was optimal when treatments were combined. This study suggests that a combination of an effective dengue antiviral along with a host-directed therapeutic may be a useful strategy to protect against dengue virus infections.