Emergence of Genotype I of Japanese Encephalitis Virus as the Dominant Genotype in Asia

Abstract

Japanese encephalitis virus (JEV), a mosquito-borne zoonotic pathogen, is one of the major causes of viral encephalitis worldwide. Previous phylogenetic studies based on the envelope protein indicated that there are four genotypes, and surveillance data suggest that genotype I is gradually replacing genotype III as the dominant strain. Here we report an evolutionary analysis based on 98 full-length genome sequences of JEV, including 67 new samples isolated from humans, pigs, mosquitoes, midges. and bats in affected areas. To investigate the relationships between the genotypes and the significance of genotype I in recent epidemics, we estimated evolutionary rates, ages of common ancestors, and population demographics. Our results indicate that the genotypes diverged in the order IV, III, II, and I and that the genetic diversity of genotype III has decreased rapidly while that of genotype I has increased gradually, consistent with its emergence as the dominant genotype.Japanese encephalitis virus (JEV), a member of the genus Flavivirus in the family Flaviviridae, is a major cause of viral encephalitis and is endemic in several regions of Asia and the Pacific (4, 13), causing an estimated 35,000 to 50,000 infections and 10,000 to 15,000 deaths annually (4, 13, 27). Fifty percent of survivors suffer from lingering neurological effects (7,27,30). Japanese encephalitis (JE) was first reported in Japan in 1924, and JE cases were subsequently reported in many other Asian countries (4,6,7,13,22,27,30). JE was first reported in Australia in 1995 (8, 9, 31). Thus, JE has become a major cause of mosquito-transmitted viral encephalitis on two continents (15,16,25).JEV, the pathogen of JE, has a genome comprising a positive-sense, single-stranded RNA molecule of approximately 11 kb that is capped at the 5Ј end and is not polyadenylated at the 3Ј end. It carries a single open reading frame (ORF) encoding a polyprotein that is processed into three structural (C, M, and E) and seven nonstructural (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) proteins, flanked by 5Ј and 3Ј nontranslated regions (NTRs) (13).Until the latter part of the 20th century, studies indicated that the predominant genotype was genotype III. Since then, there have been multiple reports of genotype I displacing genotype III in many regions (12,18,19,20,24,32,34,35), and in many areas genotype I is now recognized as the dominant strain.As part of a national encephalitis surveillance program, we collected samples from a variety of vectors (mosquitoes and midges), host animals (bats and pigs), and patients with cases of encephalitis in areas where the disease is epidemic, and we isolated viruses from a selection of the JEV-positive samples and sequenced their full genomes. We combined these sequences with other, publicly available full-length genome sequences for a final set of 98 genome sequences. With this set we performed the first detailed evolutionary analysis of JEV based on full-length genome sequences and investigated the epidemiology of genotype I relati...

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

“…However, the major genotype of JEV isolated in Japan changed from GIII to GI in the early 1990s (Ma et al, 2003;Yoshida et al, 2005). In recent years, a similar genotype shift has been observed in South Korea, northern Vietnam, China, Taiwan and Thailand Nam et al, 1996;Nga et al, 2004;Nitatpattana et al, 2008;Pan et al, 2011;Wang et al, 2007;Yang et al, 2004;Yun et al, 2010;Zhang et al, , 2011. GI JEV has also been found in India since 2009 (Fulmali et al, 2011).…”

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

“…In recent years, multiple reports have indicated that GI has displaced GIII as the most frequently isolated virus genotype in a number of Asian countries, including China (8), Thailand (9), Korea (10), Japan (11), Malaysia (12), Vietnam (13), India (14), and Taiwan (15). Although two recent evolutionary studies have examined the genotype displacement of GIII by GI in China (16,17), no studies have concurrently reconstructed the spatiotemporal chronology of the emergence of GI throughout Asia and identified genetic determinants underlying the genotype displacement as it unfolded across Asia. Furthermore, even though this geographically expansive genotype displacement is suggestive of a major difference in fitness between GIII and GI viruses, the in vitro multiplication kinetics of GIII and GI viruses have never been compared in avian or mosquito cells.…”

Genotype-specific neutralization determinants in envelope protein: implications for the improvement of Japanese encephalitis vaccine

“…Currently, GI and GIII strains represent the most prevalent genotypes in many epidemic countries. In the first half of the 20th century, the majority of JEV isolates from humans belonged to GIII; however, over the last two decades, GI has gradually replaced GIII as the dominant circulating genotype in many areas of Asia, including China, Vietnam, Japan, India and Thailand (Ma et al, 2003;Nga et al, 2004;Nitatpattana et al, 2008;Pan et al, 2011;Parida et al, 2006;Sarkar et al, 2012). The mechanism underlying the genotype displacement as well as the impact of the genotype shift on transmission/outbreak control strategies remain largely unknown (Han et al, 2014;Schuh et al, 2013Schuh et al, , 2014.…”