Abstract
The association between recent Zika virus (ZIKV) infection and neurological complications, microcephaly in the fetus, and Guillain–Barré syndrome in adults underscores the necessity for a protective vaccine. Rational vaccine development requires an in-depth understanding of the mechanisms which could protect against infection with this virus. However, so far, such an analysis has been hampered by the absence of a suitable small animal model. Unlike the situation in humans, ZIKV only replicates effectively in the peripheral organs of mice, if type I IFN signaling is interrupted. As type I IFN also impacts the adaptive immune response, mice with such a defect are not optimal for a comprehensive immunological analysis. In this report, we show that even in wild-type (WT) mice i.c. infection with low doses of virus causes marked local virus replication and lethal encephalitis in naïve mice. Furthermore, peripheral infection of WT mice with low doses of virus induces a significant immune response, which provides long-lasting protection of WT mice from a fatal outcome of subsequent i.c. challenge. Therefore, combining peripheral priming with later i.c. challenge represents a new approach for studying the adaptive immune response to ZIKV in mice with an intact type I IFN response. In this study, we focused on the mechanisms underlying resistance to reinfection. Using a combination of adoptive transfer, antibody-based cell depletion, and gene targeting, we show that the key protective factor in type I IFN replete mice is humoral immunity. CD8 T cells are not essential in mice with preformed specific antibodies, but under conditions where initial antibody levels are low, effector CD8 T cells may play a role as a back-up system. These results have important implications for our understanding of natural immunity to ZIKV infection and for Zika vaccine design.
Highlights
Zika virus (ZIKV) is one of the most recent viral pathogens to cause global public health concern
Its fast paced global spread combined with accumulating evidence linking prenatal ZIKV infection to an increased rate of babies born with microcephaly and other neurodevelopmental abnormalities led the WHO to declare it a public health emergency of international concern [8, 9]
Given that a WT mouse model would be of great importance in studying ZIKV pathogenesis, and based on our experience from working with a mouse model for yellow fever virus (YFV) [24], we wanted to investigate whether we could induce clinical disease by introducing ZIKV directly into the brain of WT mice
Summary
Zika virus (ZIKV) is one of the most recent viral pathogens to cause global public health concern. In spite of its wide geographical distribution, the virus had maintained a relatively low profile until 2007 with only 14 documented cases of human disease attributed to ZIKV infection. The ZIKV outbreak on the Micronesian island of Yap that year, which resulted in 70% of the population being infected, raised considerable concern [5]. Its fast paced global spread combined with accumulating evidence linking prenatal ZIKV infection to an increased rate of babies born with microcephaly and other neurodevelopmental abnormalities led the WHO to declare it a public health emergency of international concern [8, 9]. In addition to neonatal microcephaly, ZIKV infection has been shown to affect the adult population by attacking the peripheral nervous system and causing a neurodegenerative disease called Guillain–Barré syndrome in a few infected people [10, 11]
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