@article{d1b49fbd9d2c442c9f5db580b740d60f,
title = "A selective bottleneck shapes the evolutionary mutant spectra of enterovirus A71 during viral dissemination in humans",
abstract = "RNA viruses accumulate mutations to rapidly adapt to environmental changes. Enterovirus A71 (EV-A71) causes various clinical manifestations with occasional severe neurological complications. However, the mechanism by which EV-A71 evolves within the human body is unclear. Utilizing deep sequencing and haplotype analyses of viruses from various tissues of an autopsy patient, we sought to define the evolutionary pathway by which enterovirus A71 evolves fitness for invading the central nervous system in humans. Broad mutant spectra with divergent mutations were observed at the initial infection sites in the respiratory and digestive systems. After viral invasion, we identified a haplotype switch and dominant haplotype, with glycine at VP1 residue 31 (VP1-31G) in viral particles disseminated into the integumentary and central nervous systems. In vitro viral growth and fitness analyses indicated that VP1-31G conferred growth and a fitness advantage in human neuronal cells, whereas VP1-31D conferred enhanced replication in human colorectal cells. A higher proportion of VP1-31G was also found among fatal cases, suggesting that it may facilitate central nervous system infection in humans. Our data provide the first glimpse of EV-A71 quasispecies from oral tissues to the central nervous system within humans, showing broad implications for the surveillance and pathogenesis of this reemerging viral pathogen.",
author = "Huang, {Sheng Wen} and Huang, {Yi Hui} and Tsai, {Huey Pin} and Kuo, {Pin Hwa} and Wang, {Shih Min} and Liu, {Ching Chuan} and Wang, {Jen Ren}",
note = "Funding Information: Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwana; Department of Medical Laboratory Science and Biotechnology, National Cheng Kung University, Tainan, Taiwanb; Department of Pathology, National Cheng Kung University Hospital, Tainan, Taiwanc; Department of Emergency Medicine, National Cheng Kung University, Tainan, Taiwand; Department of Pediatrics, National Cheng Kung University, Tainan, Taiwane; National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Tainan, Taiwanf Funding Information: This work was financially supported by the Center of Infectious Disease and Signaling Research, National Cheng Kung University, Aim for the Top University Project, Ministry of Education; a Centers of Disease Control, Ministry of Health and Welfare, grant; a National Health Research Institute grant; and Ministry of Science and Technology, Taiwan, grant 105-2320-B-006-032-MY3. Computational analyses and data mining were performed using the system provided by the Bioinformatics Core at the National Cheng Kung University, supported by the Ministry of Science and Technology, Taiwan. Publisher Copyright: {\textcopyright} 2017 American Society for Microbiology.",
year = "2017",
month = dec,
day = "1",
doi = "10.1128/JVI.01062-17",
language = "English",
volume = "91",
journal = "Journal of Virology",
issn = "0022-538X",
publisher = "American Society for Microbiology",
number = "23",
}