Characterization of Full-Length Enterovirus 71 Strains from Severe and Mild Disease Patients in Northeastern China

Abstract

Human enterovirus 71 (EV71)-associated hand, foot, and mouth disease (HFMD) has been a leading cause of childhood infection in China since 2008. Epidemic and molecular characteristics of HFMD have been examined in many areas of China, including the central and southern regions. However, clinical and genetic characterization of EV71 in the northeastern region of China is scarce. In this study, a series of analyses were performed on seven full-length EV71 sequences from HFMD patients who had either severe or mild disease. We have determined that these seven circulating EV71 viruses from Changchun, China are actually complex recombinant viruses involving multiple type A human enterovirus (HEV). Classified as EV71 subtype C4 (EV71 C4), these Changchun EV71 viruses contain genetic recombination events between the CA4, CA5, EV71B4 and EV71C1 strains. Most of the structural protein region (P1) of these viruses resembled that of the prototype EV71 C1 strains. The non-structural protein domains (P2 and P3) showed a high degree of similarity with CA4, CA5 and EV71 B4 in different regions. The 5′UTR had unclassified recombination,while partial 3D region of these viruses showed a high degree of similarity to CA16. Phylogenetic analysis of full-length or partial sequences of isolates from severe or mild disease patients in Changchun always formed a single cluster in various phylogenetic analyses of different genomic regions, suggesting that all seven strains originated from one single common ancestor. There was no correlation between viral genomic sequence and virulence. Thus, we found that circulating recombinant forms of EV71 are prevalent among HFMD patients in Northeastern China. The existence of a unique cluster of EV71 related viruses in Northeast China has important implications for vaccine development that would address the increasing prevalence of HFMD.

Global Transcriptomic Analysis of Human Neuroblastoma Cells in Response to Enterovirus Type 71 Infection

“…The AH/08/06 strain is classified as subgenotype C4, which has been the sole viral genetic lineage circulating in the mainland since 2007. The strain used in this study exhibits similar recombination events as many other EV71 isolates in mainland China [39], [40], [41].…”

Co-Circulation and Genomic Recombination of Coxsackievirus A16 and Enterovirus 71 during a Large Outbreak of Hand, Foot, and Mouth Disease in Central China

“…It has been confirmed that large HFMD outbreaks with fatal neurological complications that have occurred since 2008 in China were mainly due to subgenotype C4 of EV71 [26], [60]–[62]. Enterovirus infections are generally mild, however, they have been implicated to cause a variety of diseases, ranging from asymptomatic infection, herpangina, HFMD, to more severe diseases such as menigoencephalitis, myocarditis, and neonatal sepsis, and possibly fatal encephalitis [34], [42], [49].…”

“…In China, large scale EV71 outbreaks associated with acute neurological diseases were occurred in 2008 [25], [58], and since then the outbreak pattern has repeated and exacerbated each year, with increasing morbidity and mortality [27], [59]. It has been confirmed that large HFMD outbreaks with fatal neurological complications that have occurred since 2008 are mainly due to subgenotype C4 of EV71 [26], [60]–[62].…”

Genetic and Antigenic Characterization of Enterovirus 71 in Ho Chi Minh City, Vietnam, 2011

“…VP1 genes of isolated EV71 viruses were sequenced and genotyped by phylogenetic analysis using the Neighbor-joining method in MEGA 4 software as described previously [8]. Full genomes of selected EV71 viruses were sequenced for phylogenetic analysis and detection of gene recombination [9–11]. Backgrounds of reference virus sequences used in the phylogenetic analysis were listed in the Table S1.…”