title: Identification of genetic determinants of a tick-borne flavivirus associated with host-specific adaptation and pathogenicity.
abstract: Tick-borne flaviviruses are maintained in nature in an enzootic cycle involving a tick vector and a vertebrate host. Thus, the virus replicates in two disparate hosts, each providing selective pressures that can influence virus replication and pathogenicity. To identify viral determinants associated with replication in the individual hosts, plaque purified Langat virus (TP21pp) was adapted to growth in mouse or tick cell lines to generate two virus variants, MNBp20 and ISEp20, respectively. Virus adaptation to mouse cells resulted in four amino acid changes in MNBp20 relative to TP21pp, occurring in E, NS4A and NS4B. A comparison between TP21pp and ISEp20 revealed three amino acid modifications in M, NS3 and NS4A of ISEp20. ISEp20, but not MNBp20, was attenuated following intraperitoneal inoculation of mice. Following isolation from mice brains, additional mutations reproducibly emerged in E and NS3 of ISEp20 that were possibly compensatory for the initial adaptation to tick cells. Thus, our data implicate a role for E, M, NS3, NS4A and NS4B in host adaptation and pathogenicity of tick-borne flaviviruses.
authors.affiliation: Laboratory of Virology, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 903 South Fourth Street, Hamilton, MT 59840, USA. dmitzel@niaid.nih.gov
authors.forename: Dana N
authors.initials: DN
authors.lastname: Mitzel
authors.forename: Sonja M
authors.initials: SM
authors.lastname: Best
authors.forename: Max F
authors.initials: MF
authors.lastname: Masnick
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Porcella
authors.forename: James B
authors.initials: JB
authors.lastname: Wolfinbarger
authors.forename: Marshall E
authors.initials: ME
authors.lastname: Bloom
mesh_terms: D000222:Adaptation, Physiological / Q000235:genetics; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D002460:Cell Line; D002522:Chlorocebus aethiops; D004669:Encephalitis Viruses, Tick-Borne / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology*; D004675:Encephalitis, Tick-Borne / Q000821:virology; D005838:Genotype; D018884:Ixodes / Q000166:cytology / Q000821:virology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D014709:Vero Cells; D014764:Viral Proteins / Q000737:chemistry
chemical_list: D014764:Viral Proteins