Japanese encephalitis virus E protein domain III immunization mediates cross-protection against Zika virus in mice via antibodies and CD8+T cells

Abstract

Zika virus (ZIKV) and Japanese encephalitis virus (JEV) are antigenically related flaviviruses that co-circulate in many countries/territories. The interaction between the two viruses needs to be determined. Recent findings by ourselves and other labs showed that JEV-elicited antibodies (Abs) and CD8⁺T cells exacerbate and protect against subsequent ZIKV infection, respectively. However, the impact of JEV envelope (E) protein domain III (EDIII)-induced immune responses on ZIKV infection is unclear. We show here that sera from JEV-EDIII-vaccinated mice cross-react with ZIKV-EDIII in vitro, and transfer of the same sera to mice significantly decreases death upon lethal ZIKV infection at a dose-dependent manner. Maternally acquired anti-JEV-EDIII Abs also significantly reduce the mortality of neonatal mice born to JEV-EDIII-immune mothers post ZIKV challenge. Similarly, transfer of ZIKV-EDIII-reactive IgG purified from JEV-vaccinated humans increases the survival of ZIKV-infected mice. Notably, transfer of an extremely low volume of JEV-EDIII-immune sera or ZIKV-EDIII-reactive IgG does not mediate the Ab-mediated enhancement (ADE) of ZIKV infection. Similarly, transfer of JEV-EDIII-elicited CD8⁺T cells protects recipient mice against ZIKV challenge. These results demonstrate that JEV-EDIII-induced immune components including Abs and T cells have protective roles in ZIKV infection, suggesting EDIII is a promising immunogen for developing effective and safety JEV vaccine.

Keywords: CD8(+)T cells; Envelope protein domain III; Japanese encephalitis virus; Zika virus.

Fig. 1

Sera from JEV-EDIII-immune mice contain JEV-EDIII- and ZIKV-EDIII-reactive IgG.

Fig. 2

Cross-neutralization of ZIKV infection in vitro by JEV-EDIII-immune mouse sera.

Fig. 3

Transfer of JEV-EDIII-immune mouse sera increases the survival of JEV-infected and ZIKV-infected mice.

Fig. 4

Transfer of ZIKV-EDIII-reactive IgG purified from human JEV-immune sera protects against ZIKV infection in mice.

Fig. 5

Pups born to JEV-EDIII-immune mothers have increased survival upon ZIKV challenge compared with pups born to mock-immune mothers.

Fig. 6

Transfer of JEV-EDIII-elicited CD8⁺T cells increases the survival of JEV-infected and ZIKV-infected mice.