The Japanese Encephalitis Antigenic Complex Viruses: From Structure to Immunity

Abstract

In the last three decades, several flaviviruses of concern that belong to different antigenic groups have expanded geographically. This has resulted in the presence of often more than one virus from a single antigenic group in some areas, while in Europe, Africa and Australia, additionally, multiple viruses belonging to the Japanese encephalitis (JE) serogroup co-circulate. Morphological heterogeneity of flaviviruses dictates antibody recognition and affects virus neutralization, which influences infection control. The latter is further impacted by sequential infections involving diverse flaviviruses co-circulating within a region and their cross-reactivity. The ensuing complex molecular virus-host interplay leads to either cross-protection or disease enhancement; however, the molecular determinants and mechanisms driving these outcomes are unclear. In this review, we provide an overview of the epidemiology of four JE serocomplex viruses, parameters affecting flaviviral heterogeneity and antibody recognition, host immune responses and the current knowledge of the cross-reactivity involving JE serocomplex flaviviruses that leads to differential clinical outcomes, which may inform future preventative and therapeutic interventions.

Keywords: Japanese encephalitis serogroup; Japanese encephalitis virus; Murray valley encephalitis virus; Usutu virus; West Nile virus; cross-reactivity; envelope protein.

Figure 1

Global distribution of flaviviruses. Multiple flaviviruses co-circulate in most continents; of these, at least one virus belongs to the JE serocomplex. Co-circulation of more than one JE serocomplex virus occurs in Africa, Europe, Asia and Australia. The figure was generated using an online tool, URL: https://mapchart.net. (DENV: Dengue virus; IHLV: Ilheus virus; JEV: Japanese encephalitis virus; MVEV: Murray valley encephalitis virus; POWV: Powassan virus; ROCV: Rocio virus; SPOV: Spondwenii virus; USUV: Usutu virus; WSLV: Wesselsbron virus; WNV: West nile virus; YFV: Yellow fever virus; ZIKV: Zika virus).

Figure 2

Models of the flavivirus structural proteins corresponding to various stages in the virus life cycle. (A–C): Immature DENV1 trimer, mature USUV dimer and the fusogenic DENV hairpin conformation, respectively. Corresponding top views are depicted in (D–F), respectively. For the immature E trimer and the E dimer, the E-stem region is also shown. The models are color coded as follows: DI (red), DII (yellow), DIII (blue), fusion loop (green), glycosylation sites (orange) and prM (cyan); for (B,E), the E-stem is in light blue and M protein is in teal.

Figure 3

Models of some JE serocomplex flavivirus particles with bound Fabs. (A). Immature WNV particle with bound E53, which is cross-reactive and preferentially binds immature flavivirus particle but not the mature particles. The Fab chains are depicted in green and light green. (B). Mature WNV with bound CR4354, which binds two neighboring E molecules and neutralizes by blocking the conformational rearrangement essential for membrane fusion. Fab chains are shown in blue and light blue.