title: Rift Valley fever virus MP-12 vaccine encoding Toscana virus NSs retains neuroinvasiveness in mice.
abstract: Rift Valley fever is a mosquito-borne zoonotic disease endemic to sub-Saharan Africa. Rift Valley fever virus (RVFV; genus Phlebovirus, family Bunyaviridae) causes high rates of abortion and fetal malformation in pregnant ruminants, and haemorrhagic fever, neurological disorders or blindness in humans. The MP-12 strain is a highly efficacious and safe live-attenuated vaccine candidate for both humans and ruminants. However, MP-12 lacks a marker to differentiate infected from vaccinated animals. In this study, we originally aimed to characterize the efficacy of a recombinant RVFV MP-12 strain encoding Toscana virus (TOSV) NSs gene in place of MP-12 NSs (rMP12-TOSNSs). TOSV NSs promotes the degradation of dsRNA-dependent protein kinase (PKR) and inhibits interferon-β gene up-regulation without suppressing host general transcription. Unexpectedly, rMP12-TOSNSs increased death in vaccinated outbred mice and inbred BALB/c or C57BL/6 mice. Immunohistochemistry showed diffusely positive viral antigens in the thalamus, hypothalamus and brainstem, including the medulla. No viral antigens were detected in spleen or liver, which is similar to the antigen distribution of moribund mice infected with MP-12. These results suggest that rMP12-TOSNSs retains neuroinvasiveness in mice. Our findings demonstrate that rMP12-TOSNSs causes neuroinvasion without any hepatic disease and will be useful for studying the neuroinvasion mechanism of RVFV and TOSV.
authors.affiliation: Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Sabarish V
authors.initials: SV
authors.lastname: Indran
authors.affiliation: Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Olga A
authors.initials: OA
authors.lastname: Lihoradova
authors.affiliation: Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Inaia
authors.initials: I
authors.lastname: Phoenix
authors.affiliation: Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Nandadeva
authors.initials: N
authors.lastname: Lokugamage
authors.affiliation: Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Birte
authors.initials: B
authors.lastname: Kalveram
authors.affiliation: Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Head
authors.affiliation: Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Bersabeh
authors.initials: B
authors.lastname: Tigabu
authors.affiliation: Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas, USA.|Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Smith
authors.affiliation: Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas, USA.|Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Lihong
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas, USA.|Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Terry L
authors.initials: TL
authors.lastname: Juelich
authors.affiliation: Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas, USA.|Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Gong
authors.affiliation: Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, Texas, USA.|Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch, Galveston, Texas, USA.|Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA.|Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Alexander N
authors.initials: AN
authors.lastname: Freiberg
authors.affiliation: Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch, Galveston, Texas, USA.|Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, Texas, USA.|Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Ikegami
mesh_terms: D000818:Animals; D001921:Brain / Q000821:virology*; D002460:Cell Line; D002522:Chlorocebus aethiops; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009422:Nervous System Diseases / Q000821:virology*; D012295:Rift Valley Fever / Q000276:immunology / Q000517:prevention & control*; D012296:Rift Valley fever virus / Q000276:immunology; D029301:Sandfly fever Naples virus / Q000235:genetics* / Q000276:immunology / Q000472:pathogenicity*; D014611:Vaccination; D014613:Vaccines, Attenuated / Q000008:administration & dosage / Q000009:adverse effects* / Q000276:immunology; D014709:Vero Cells; D017361:Viral Nonstructural Proteins / Q000276:immunology / Q000378:metabolism*; D014765:Viral Vaccines / Q000008:administration & dosage / Q000009:adverse effects* / Q000276:immunology
chemical_list: D007074:Immunoglobulin G; D014613:Vaccines, Attenuated; D017361:Viral Nonstructural Proteins; D014765:Viral Vaccines