Zika Virus Fatally Infects Wild Type Neonatal Mice and Replicates in Central Nervous System

Abstract

Zika virus (ZIKV) has been defined as a teratogenic pathogen behind the increased number of cases of microcephaly in French Polynesia, Brazil, Puerto Rico, and other South American countries. Experimental studies using animal models have achieved tremendous insight into understanding the viral pathogenesis, transmission, teratogenic mechanisms, and virus–host interactions. However, the animals used in published investigations are mostly interferon (IFN)-compromised, either genetically or via antibody treatment. Herein, we studied ZIKV infection in IFN-competent mice using African (MR766) and Asian strains (PRVABC59 and SZ-WIV01). After testing four different species of mice, we found that BALB/c neonatal mice were resistant to ZIKV infection, that Kunming, ICR and C57BL/6 neonatal mice were fatally susceptible to ZIKV infection, and that the fatality of C57BL/6 neonates from 1 to 3 days old were in a viral dose-dependent manner. The size and weight of the brain were significantly reduced, and the ZIKV-infected mice showed neuronal symptoms such as hind-limb paralysis, tremor, and poor balance during walking. Pathologic and immunofluorescent experiments revealed that ZIKV infected different areas of the central nervous system (CNS) including gray matter, hippocampus, cerebral cortex, and spinal cord, but not olfactory bulb. Interestingly, ZIKV replicated in multiple organs and resulted in pathogenesis in liver and testis, implying that ZIKV infection may engender a high health risk in neonates by postnatal infection. In summary, we investigated ZIKV pathogenesis using an animal model that is not IFN-compromised.

Genetic diversity of Collaborative Cross mice controls viral replication, clinical severity and brain pathology induced by Zika virus infection, independently of Oas1b

“…To overcome the inability of ZIKV to inhibit in mice IFN induction and signaling pathways as observed in humans (27), most studies have been performed using Ifnar1 -deficient mice which have become a reference model. However, high levels of viral replication can also be achieved by temporary inhibition of IFN signaling by anti-IFNAR mAb treatment (30, 31, 61) or even in immunocompetent mice by infecting neonates (36, 62–64) or using a combination of mouse-adapted ZIKV strains and human STAT2 knock-in mice (65).…”

Japanese encephalitis virus–primed CD8+ T cells prevent antibody-dependent enhancement of Zika virus pathogenesis

“…Next, we examined whether JEV-immune sera could promote ADE of ZIKV infection in vivo as well as in vitro. For these experiments, we selected 1-d-old WT mice because ZIKV infection is lethal in neonates but not in adults (Li et al, 2018;Manangeeswaran et al, 2016). Although the precise reasons for this differential Figure 1.…”

Mathematical modeling of within‐host Zika virus dynamics

“…In order to obtain productive infection in adult mice, type I interferon (IFN) responses generally need to be knocked out . Similarly, wildtype neonatal mice who possess undeveloped immune systems are able to be infected, with pathogenesis being both dose and age dependent. In humans, ZIKV is able to suppress the type I IFN response by targeting the transcriptional activator STAT2 for proteasomal degradation, but this does not occur in mice, which may explain the requirement of knocking out the IFN response in mice to generate productive infection .…”