Dynamics of the Emergence and Establishment of a Newly Dominant Genotype of Japanese Encephalitis Virus throughout Asia

Abstract

In recent years, genotype I (GI) of Japanese encephalitis virus (JEV) has displaced genotype III (GIII) as the dominant virus genotype throughout Asia. In this study, the largest collection of GIII and GI envelope gene-derived viral sequences assembled to date was used to reconstruct the spatiotemporal chronology of genotype displacement throughout Asia and to determine the evolutionary and epidemiological dynamics underlying this significant event. GI consists of two clades, GI-a and GI-b, with the latter being associated with displacement of GIII as the dominant JEV genotype throughout Asia in the 1990s. Phylogeographic analysis indicated that GI-a diverged in Thailand or Cambodia and has remained confined to tropical Asia, whereas GI-b diverged in Vietnam and then dispersed northwards to China, where it was subsequently dispersed to Japan, Korea, and Taiwan. Molecular adaptation was detected by more than one method at one site (residue 15), and coevolution was detected at two pairs of sites (residues 89 to 360 and 129 to 141) within the GI E gene protein alignment. Viral multiplication and temperature sensitivity analyses in avian and mosquito cells revealed that the GI-b isolate JE-91 had significantly higher infectivity titers in mosquito cells from 24 to 48 h postinfection than did the GI-a and GIII isolates. If the JE-91 isolate is indeed representative of GI-b, an increased multiplicative ability of GI-b viruses compared to that of GIII viruses early in mosquito infection may have resulted in a shortened extrinsic incubation period that led to an increased number of GI enzootic transmission cycles and the subsequent displacement of GIII. IMPORTANCE Japanese encephalitis virus (JEV), a mosquito-borne flavivirus, represents the most significant etiology of childhood viral neurological infection in Asia.Despite the existence of effective vaccines, JEV is responsible for an estimated 68,000 human cases and a reported 10,000 to 15,000 deaths annually. Phylogenetic studies divided JEV into five geographically and epidemiologically distinct genotypes (GI to GV). GIII has been the source of numerous JEV epidemics throughout history and was the most frequently isolated genotype throughout most of Asia from 1935 until the 1990s. In recent years, GI has displaced GIII as the most frequently isolated virus genotype. To date, the mechanism of this genotype replacement has remained unknown. In this study, we have identified genetic determinants underlying the genotype displacement as it unfolded across Asia. JEV provides a paradigm for other flaviviruses, including West Nile, yellow fever, and dengue viruses, and the critical role of the selective advantages in the mosquito vector.

Increased Replicative Fitness of a Dengue Virus 2 Clade in Native Mosquitoes: Potential Contribution to a Clade Replacement Event in Nicaragua

“…Alternatively, stochastic events leading to a genetic bottleneck event within or among hosts may also lead to the emergence of new genetic variants that could compete with existing viral populations and may ultimately form new genetic clades. Such replacement events are not unique to DENV and have also been reported for other flaviviruses, such as Japanese encephalitis and West Nile viruses (25)(26)(27).…”

In vitro growth, pathogenicity and serological characteristics of the Japanese encephalitis virus genotype V Muar strain

“…The Indonesian/Malaysian region is thought to be the origin of all genotypes of JEV (Solomon et al, 2003), and in several South-east Asian countries, GI was isolated as a minor JEV strain before the 1990s. Comprehensive phylogenetic analysis of the GI JEV strains has demonstrated that the old and the new GI strains form distinct lineages (Gao et al, 2013;Schuh et al, 2014), suggesting that genetic differences in the new GI genome might be responsible for the spread of GI viruses. Recent findings indicate that GI JEV exhibits a higher replicative ability in mosquitoes than GIII JEV (Schuh et al, 2014).…”

Comparison of Genotypes I and III in Japanese Encephalitis Virus Reveals Distinct Differences in Their Genetic and Host Diversity

“…However, a recent study of E protein gene sequences revealed that genotype I could be subdivided into two clades, GI-a and GI-b, with the majority of isolates placed in GI-b. Furthermore, viral multiplication and temperature sensitivity analyses revealed that the GI-b isolate had significantly higher infectivity titers in mosquito cells from 24 to 48 h postinfection, providing new insight into how GI emerged as the dominant lineage (23). Nevertheless, the recent publication of a large number of whole-genome sequences of JEV and the availability of a very large number of sequences from other genes make further examination of the GIII-to-GI displacement event worthwhile.…”