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

Abstract

Cross-reactive anti-flaviviral immunity can influence the outcome of infections with heterologous flaviviruses. However, it is unclear how the interplay between cross-reactive antibodies and T cells tilts the balance toward pathogenesis versus protection during secondary Zika virus (ZIKV) and Japanese encephalitis virus (JEV) infections. We show that sera and IgG from JEV-vaccinated humans and JEV-inoculated mice cross-reacted with ZIKV, exacerbated lethal ZIKV infection upon transfer to mice, and promoted viral replication and mortality upon ZIKV infection of the neonates born to immune mothers. In contrast, transfer of CD8+ T cells from JEV-exposed mice was protective, reducing the viral burden and mortality of ZIKV-infected mice and abrogating the lethal effects of antibody-mediated enhancement of ZIKV infection in mice. Conversely, cross-reactive anti-ZIKV antibodies or CD8+ T cells displayed the same pathogenic or protective effects upon JEV infection, with the exception that maternally acquired anti-ZIKV antibodies had no effect on JEV infection of the neonates. These results provide clues for developing safe anti-JEV/ZIKV vaccines.

Japanese Encephalitis Virus Vaccination Elicits Cross-Reactive HLA-Class I-Restricted CD8 T Cell Response Against Zika Virus Infection

“…It has been shown in Dengue virus infection, efficient CD8 T cells response is sufficient to inhibit ADE in infected mice. Our present study together with previous findings (18,24) all suggest that cross-reactive JEV-specific CD8 T cells are protective to ZIKV infection in wild-type mice that are not HLA-transgenic (18,19,25). Thus, JEV vaccine can be clinically used for the prevention of ZIKV infection and also is at low risk of ADE induction in immune-competent humans.…”

“…Additionally, CD8 T cells in JEV-vaccinated and JEV-exposed healthy human subjects cross-react with DVs ( 16 , 17 ) and other flaviviruses. Furthermore, Recent studies have revealed that murine MHC I-restricted CD8 T cells from mice infected with JEV or vaccine strain are indeed cross-reactive with ZIKV ( 18 , 19 ). These evidences suggest JEV vaccination may elicit cross-reactive T cell immunity against ZIKV and thereby affect ZIKV pathogenesis in humans.…”

Cross-Reactive Immunity among Five Medically Important Mosquito-Borne Flaviviruses Related to Human Diseases

“…(1) In vitro serological experiment ELISA testing proved that sera of JEV-immune mice or humans contained ZIKV crossreactive antibodies, and He, et al demonstrated that the titers of JEV antibodies were positively correlated with the titers of ZIKV cross-reactive antibodies in ZIKV non-endemic areas [6,42]. However, few cross-reactive NAbs against ZIKV were present in JEV-immune sera, and JEV-immune human and mouse sera could induce ADE of ZIKV in vitro [6,43].…”

“…(2) In vivo mouse model By sequential infection of JEV-ZIKV and passive administration of JEV antisera in the ifnar −/− mouse model, Zhang, et al reported that the immune history of JE LAV could protect the mice against ZIKV infection without the mediation of cross-reactive antibodies [6]. Passive transfer of highly diluted sera of JE LAV immune humans or rabbits exacerbated ZIKV infection in the ifnar1 transiently blockaded mouse model [42,43]. Additionally, neonates of JEV-immune female mice showed higher mortality and viremia level than neonates of non-immune mice when challenged with ZIKV [43], suggesting that the anti-JEV IgG antibody from pregnant mice caused ADE of ZIKV in neonates.…”

A Zika virus mutation enhances transmission potential and confers escape from protective dengue virus immunity

“…Sequential infection by two different DENV serotypes or by ZIKV followed by DENV is known to be a major risk factor for severe dengue, in part due to the phenomenon of Ab-dependent enhancement of infection induced by pre-existing anti-flaviviral immunity ( Halstead, 2007 ; Katzelnick et al, 2017 , 2020 ; Salje et al, 2018 ). The robustness of the immune response elicited by prior DENV exposure can influence ZIKV infection outcome, through T cell-mediated cross-protection against ZIKV and antibody-mediated enhancement of ZIKV pathogenesis ( Bardina et al, 2017 ; Chen et al, 2020 ; Gordon et al, 2019 ; Pedroso et al, 2019 ; Rathore et al, 2019 ; Regla-Nava et al, 2018 ; Rodriguez-Barraquer et al, 2019 ; Valentine et al, 2020 ; Wen et al, 2017a , 2017b , 2020 ). The present study reveals that ZIKV can readily adapt to enhance its virulence not only in a naive host but also in the presence of pre-existing cross-protective DENV immunity.…”