title: Rapid accumulation of virulent rift valley Fever virus in mice from an attenuated virus carrying a single nucleotide substitution in the m RNA.
abstract: BACKGROUND
  Rift Valley fever virus (RVFV), a member of the genus Phlebovirus within the family Bunyaviridae, is a negative-stranded RNA virus with a tripartite genome. RVFV is transmitted by mosquitoes and causes fever and severe hemorrhagic illness among humans, while in livestock it causes fever and high abortion rates.
  
  
  RESULTS
  Sequence analysis showed that a wild-type RVFV ZH501 preparation consisted of two major viral subpopulations, with a single nucleotide heterogeneity at nucleotide 847 of M segment (M847); one had a G residue at M847 encoding glycine in a major viral envelope Gn protein, while the other carried A residue encoding glutamic acid at the corresponding site. Two ZH501-derived viruses, rZH501-M847-G and rZH501-M847-A, carried identical genomic sequences, except that the former and the latter had G and A, respectively, at M847 were recovered by using a reverse genetics system. Intraperitoneal inoculation of rZH501-M847-A into mice caused a rapid and efficient viral accumulation in the sera, livers, spleens, kidneys and brains, and killed most of the mice within 8 days, whereas rZH501-M847-G caused low viremia titers, did not replicate as efficiently as did rZH501-M847-A in these organs, and had attenuated virulence to mice. Remarkably, as early as 2 days postinfection with rZH501-M847-G, the viruses carrying A at M847 emerged and became the major virus population thereafter, while replicating viruses retained the input A residue at M847 in rZH501-M847-A-infected mice.
  
  
  CONCLUSIONS
  These data demonstrated that the single nucleotide substitution in the Gn protein substantially affected the RVFV mouse virulence and that a virus population carrying the virulent viral genotype quickly emerged and became the major viral population within a few days in mice that were inoculated with the attenuated virus.
authors.affiliation: Department of Microbiology and Immunology, The University of Texas Medical Branch at Galveston, Galveston, Texas, United States of America.
authors.forename: John C
authors.initials: JC
authors.lastname: Morrill
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Ikegami
authors.forename: Naoko
authors.initials: N
authors.lastname: Yoshikawa-Iwata
authors.forename: Nandadeva
authors.initials: N
authors.lastname: Lokugamage
authors.forename: Sungyong
authors.initials: S
authors.lastname: Won
authors.forename: Kaori
authors.initials: K
authors.lastname: Terasaki
authors.forename: Aya
authors.initials: A
authors.lastname: Zamoto-Niikura
authors.forename: C J
authors.initials: CJ
authors.lastname: Peters
authors.forename: Shinji
authors.initials: S
authors.lastname: Makino
mesh_terms: D000818:Animals; D016679:Genome, Viral; D051379:Mice; D017354:Point Mutation; D020641:Polymorphism, Single Nucleotide; D012367:RNA, Viral / Q000235:genetics*; D012296:Rift Valley fever virus / Q000235:genetics* / Q000472:pathogenicity*; D014613:Vaccines, Attenuated / Q000009:adverse effects; D014774:Virulence / Q000235:genetics
chemical_list: D012367:RNA, Viral; D014613:Vaccines, Attenuated