title: Attenuation of pathogenic Rift Valley fever virus strain through the chimeric S-segment encoding sandfly fever phlebovirus NSs or a dominant-negative PKR.
abstract: Rift Valley fever is a mosquito-borne zoonotic disease affecting ruminants and humans. Rift Valley fever virus (RVFV: family Bunyaviridae, genus Phlebovirus) causes abortions and fetal malformations in ruminants, and hemorrhagic fever, encephalitis, or retinitis in humans. The live-attenuated MP-12 vaccine is conditionally licensed for veterinary use in the US. However, this vaccine lacks a marker for the differentiation of vaccinated from infected animals (DIVA). NSs gene is dispensable for RVFV replication, and thus, rMP-12 strains lacking NSs gene is applicable to monitor vaccinated animals. However, the immunogenicity of MP-12 lacking NSs was not as high as parental MP-12. Thus, chimeric MP-12 strains encoding NSs from either Toscana virus (TOSV), sandfly fever Sicilian virus (SFSV) or Punta Toro virus Adames strain (PTA) were characterized previously. Although chimeric MP-12 strains are highly immunogenic, the attenuation through the S-segment remains unknown. Using pathogenic ZH501 strain, we aimed to demonstrate the attenuation of ZH501 strain through chimeric S-segment encoding either the NSs of TOSV, SFSV, PTA, or Punta Toro virus Balliet strain (PTB). In addition, we characterized rZH501 encoding a human dominant-negative PKR (PKRΔE7), which also enhances the immunogenicity of MP-12. Study done on mice revealed that attenuation of rZH501 occurred through the S-segment encoding either PKRΔE7 or SFSV NSs. However, rZH501 encoding either TOSV, PTA, or PTB NSs in the S-segment uniformly caused lethal encephalitis. Our results indicated that the S-segments encoding PKRΔE7 or SFSV NSs are attenuated and thus applicable toward next generation MP-12 vaccine candidates that encode a DIVA marker.
authors.affiliation: a Department of Pathology , The University of Texas Medical Branch at Galveston , Galveston , TX , USA.
authors.forename: Shoko
authors.initials: S
authors.lastname: Nishiyama
authors.affiliation: a Department of Pathology , The University of Texas Medical Branch at Galveston , Galveston , TX , USA.
authors.forename: Olga A L
authors.initials: OA
authors.lastname: Slack
authors.affiliation: a Department of Pathology , The University of Texas Medical Branch at Galveston , Galveston , TX , USA.
authors.forename: Nandadeva
authors.initials: N
authors.lastname: Lokugamage
authors.affiliation: a Department of Pathology , The University of Texas Medical Branch at Galveston , Galveston , TX , USA.
authors.forename: Terence E
authors.initials: TE
authors.lastname: Hill
authors.affiliation: a Department of Pathology , The University of Texas Medical Branch at Galveston , Galveston , TX , USA.|b Galveston National Laboratory, The University of Texas Medical Branch at Galveston , Galveston , TX , USA.
authors.forename: Terry L
authors.initials: TL
authors.lastname: Juelich
authors.affiliation: a Department of Pathology , The University of Texas Medical Branch at Galveston , Galveston , TX , USA.|b Galveston National Laboratory, The University of Texas Medical Branch at Galveston , Galveston , TX , USA.
authors.forename: Lihong
authors.initials: L
authors.lastname: Zhang
authors.affiliation: a Department of Pathology , The University of Texas Medical Branch at Galveston , Galveston , TX , USA.|b Galveston National Laboratory, The University of Texas Medical Branch at Galveston , Galveston , TX , USA.
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Smith
authors.affiliation: a Department of Pathology , The University of Texas Medical Branch at Galveston , Galveston , TX , USA.
authors.forename: David
authors.initials: D
authors.lastname: Perez
authors.affiliation: a Department of Pathology , The University of Texas Medical Branch at Galveston , Galveston , TX , USA.|b Galveston National Laboratory, The University of Texas Medical Branch at Galveston , Galveston , TX , USA.|c The Center for Biodefense and Emerging Infectious Diseases, The University of Texas Medical Branch at Galveston , Galveston , TX , USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Gong
authors.affiliation: a Department of Pathology , The University of Texas Medical Branch at Galveston , Galveston , TX , USA.|b Galveston National Laboratory, The University of Texas Medical Branch at Galveston , Galveston , TX , USA.|c The Center for Biodefense and Emerging Infectious Diseases, The University of Texas Medical Branch at Galveston , Galveston , TX , USA.|d The Sealy Center for Vaccine Development, The University of Texas Medical Branch at Galveston , Galveston , TX , USA.
authors.forename: Alexander N
authors.initials: AN
authors.lastname: Freiberg
authors.affiliation: a Department of Pathology , The University of Texas Medical Branch at Galveston , Galveston , TX , USA.|c The Center for Biodefense and Emerging Infectious Diseases, The University of Texas Medical Branch at Galveston , Galveston , TX , USA.|d The Sealy Center for Vaccine Development, The University of Texas Medical Branch at Galveston , Galveston , TX , USA.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Ikegami
mesh_terms: D000818:Animals; D002460:Cell Line; D002522:Chlorocebus aethiops; D006801:Humans; D000071497:Immunogenicity, Vaccine; D051379:Mice; D011993:Recombinant Fusion Proteins / Q000276:immunology; D012296:Rift Valley fever virus / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity*; D029301:Sandfly fever Naples virus / Q000235:genetics; D014613:Vaccines, Attenuated / Q000235:genetics / Q000276:immunology; D014709:Vero Cells; D017361:Viral Nonstructural Proteins / Q000235:genetics* / Q000276:immunology*; D014765:Viral Vaccines / Q000235:genetics / Q000276:immunology*
chemical_list: D011993:Recombinant Fusion Proteins; D014613:Vaccines, Attenuated; D017361:Viral Nonstructural Proteins; D014765:Viral Vaccines
keywords: NSs; PKR; Rift valley fever virus; Toscana virus; attenuation; phlebovirus; punta toro virus; sandfly fever Sicilian virus; vaccine