title: The dominant-negative inhibition of double-stranded RNA-dependent protein kinase PKR increases the efficacy of Rift Valley fever virus MP-12 vaccine.
abstract: Rift Valley fever virus (RVFV), belonging to the genus Phlebovirus, family Bunyaviridae, is endemic to sub-Saharan Africa and causes a high rate of abortion in ruminants and hemorrhagic fever, encephalitis, or blindness in humans. MP-12 is the only RVFV strain excluded from the select-agent rule and handled at a biosafety level 2 (BSL2) laboratory. MP-12 encodes a functional major virulence factor, the NSs protein, which contributes to its residual virulence in pregnant ewes. We found that 100% of mice subcutaneously vaccinated with recombinant MP-12 (rMP12)-murine PKRN167 (mPKRN167), which encodes a dominant-negative form of mouse double-stranded RNA (dsRNA)-dependent protein kinase (PKR) in place of NSs, were protected from wild-type (wt) RVFV challenge, while 72% of mice vaccinated with MP-12 were protected after challenge. rMP12-mPKRN167 induced alpha interferon (IFN-α) in sera, accumulated RVFV antigens in dendritic cells at the local draining lymph nodes, and developed high levels of neutralizing antibodies, while parental MP-12 induced neither IFN-α nor viral-antigen accumulation at the draining lymph node yet induced a high level of neutralizing antibodies. The present study suggests that the expression of a dominant-negative PKR increases the immunogenicity and efficacy of live-attenuated RVFV vaccine, which will lead to rational design of safe and highly immunogenic RVFV vaccines for livestock and humans.
authors.affiliation: Department of Pathology, Galveston, TX, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Lihoradova
authors.forename: Birte
authors.initials: B
authors.lastname: Kalveram
authors.forename: Sabarish V
authors.initials: SV
authors.lastname: Indran
authors.forename: Nandadeva
authors.initials: N
authors.lastname: Lokugamage
authors.forename: Terry L
authors.initials: TL
authors.lastname: Juelich
authors.forename: Terence E
authors.initials: TE
authors.lastname: Hill
authors.forename: Chien-Te K
authors.initials: CT
authors.lastname: Tseng
authors.forename: Bin
authors.initials: B
authors.lastname: Gong
authors.forename: Shuetsu
authors.initials: S
authors.lastname: Fukushi
authors.forename: Shigeru
authors.initials: S
authors.lastname: Morikawa
authors.forename: Alexander N
authors.initials: AN
authors.lastname: Freiberg
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Ikegami
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D002460:Cell Line; D018925:Chemokines / Q000097:blood; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003713:Dendritic Cells / Q000276:immunology; D016898:Interferon-alpha / Q000097:blood; D007371:Interferon-gamma / Q000097:blood; D020381:Interleukin-17 / Q000097:blood; D015848:Interleukin-5 / Q000097:blood; D051379:Mice; D009154:Mutation; D012296:Rift Valley fever virus / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity; D014709:Vero Cells; D017361:Viral Nonstructural Proteins / Q000276:immunology*; D014765:Viral Vaccines / Q000276:immunology*; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors / Q000276:immunology*
chemical_list: D057134:Antibodies, Neutralizing; D018925:Chemokines; D016898:Interferon-alpha; D020381:Interleukin-17; D015848:Interleukin-5; D017361:Viral Nonstructural Proteins; D014765:Viral Vaccines; D007371:Interferon-gamma; D019892:eIF-2 Kinase