title: The role of the poly(A) tract in the replication and virulence of tick-borne encephalitis virus.
abstract: The tick-borne encephalitis virus (TBEV) is a flavivirus transmitted to humans, usually via tick bites. The virus causes tick-borne encephalitis (TBE) in humans, and symptoms range from mild flu-like symptoms to severe and long-lasting sequelae, including permanent brain damage. It has been suggested that within the population of viruses transmitted to the mammalian host, quasispecies with neurotropic properties might become dominant in the host resulting in neurological symptoms. We previously demonstrated the existence of TBEV variants with variable poly(A) tracts within a single blood-fed tick. To characterize the role of the poly(A) tract in TBEV replication and virulence, we generated infectious clones of Torö-2003 with the wild-type (A)3C(A)6sequence (Torö-6A) or with a modified (A)3C(A)38sequence (Torö-38A). Torö-38A replicated poorly compared to Torö-6A in cell culture, but Torö-38A was more virulent than Torö-6A in a mouse model of TBE. Next-generation sequencing of TBEV genomes after passaging in cell culture and/or mouse brain revealed mutations in specific genomic regions and the presence of quasispecies that might contribute to the observed differences in virulence. These data suggest a role for quasispecies development within the poly(A) tract as a virulence determinant for TBEV in mice.
authors.affiliation: Södertörn University, School of Natural Science, Technology &Environmental Studies, Huddinge, 14189, Sweden.|Örebro University, School of Medical Sciences, Örebro, 70182, Sweden.|Örebro University, iRiSC - Inflammatory Response and Infection Susceptibility Centre, Faculty of Medicine and Health, Örebro, 70182, Sweden.
authors.forename: Naveed
authors.initials: N
authors.lastname: Asghar
authors.affiliation: Umeå University, Department of Clinical Microbiology, Virology, Umeå, 90185, Sweden.|Umeå University, The Laboratory for Molecular Medicine Sweden (MIMS), Umeå, 90185, Sweden.
authors.forename: Yi-Ping
authors.initials: YP
authors.lastname: Lee
authors.affiliation: Umeå University, Department of Clinical Microbiology, Virology, Umeå, 90185, Sweden.|Umeå University, The Laboratory for Molecular Medicine Sweden (MIMS), Umeå, 90185, Sweden.
authors.forename: Emma
authors.initials: E
authors.lastname: Nilsson
authors.affiliation: Umeå University, Department of Clinical Microbiology, Virology, Umeå, 90185, Sweden.|Umeå University, The Laboratory for Molecular Medicine Sweden (MIMS), Umeå, 90185, Sweden.
authors.forename: Richard
authors.initials: R
authors.lastname: Lindqvist
authors.affiliation: Örebro University, School of Medical Sciences, Örebro, 70182, Sweden.|Örebro University, iRiSC - Inflammatory Response and Infection Susceptibility Centre, Faculty of Medicine and Health, Örebro, 70182, Sweden.
authors.forename: Wessam
authors.initials: W
authors.lastname: Melik
authors.affiliation: Helmholtz Centre for Infection Research, Innate Immunity and Infection, Braunschweig, 38124, Germany.|University of Magdeburg, Institute for Microbiology, Magdeburg, 39120, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Kröger
authors.affiliation: Umeå University, Department of Clinical Microbiology, Virology, Umeå, 90185, Sweden.|Umeå University, The Laboratory for Molecular Medicine Sweden (MIMS), Umeå, 90185, Sweden.
authors.forename: Anna K
authors.initials: AK
authors.lastname: Överby
authors.affiliation: Örebro University, School of Medical Sciences, Örebro, 70182, Sweden.|Örebro University, iRiSC - Inflammatory Response and Infection Susceptibility Centre, Faculty of Medicine and Health, Örebro, 70182, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Johansson
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000072283:A549 Cells; D000818:Animals; D001483:Base Sequence; D002522:Chlorocebus aethiops; D004669:Encephalitis Viruses, Tick-Borne / Q000235:genetics* / Q000472:pathogenicity / Q000502:physiology; D004675:Encephalitis, Tick-Borne / Q000473:pathology / Q000662:veterinary / Q000821:virology; D016679:Genome, Viral; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D010957:Plasmids / Q000235:genetics / Q000378:metabolism; D011061:Poly A / Q000235:genetics*; D012367:RNA, Viral / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D016415:Sequence Alignment; D013987:Ticks / Q000821:virology; D014709:Vero Cells; D014774:Virulence; D014779:Virus Replication
chemical_list: D020413:3' Untranslated Regions; D012367:RNA, Viral; D011061:Poly A