The dominant-negative inhibition of double-stranded RNA-dependent protein kinase PKR increases the efficacy of rift valley fever virus MP-12 vaccine

Olga Lihoradova, Birte Kalveram, Sabarish V. Indran, Nandadeva Lokugamage, Terry L. Juelich, Terence E. Hill, Chien Te K. Tseng, Bin Gong, Shuetsu Fukushi, Shigeru Morikawa, Alexander N. Freiberg, Tetsuro Ikegami

Research output: Contribution to journalArticle

18 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)7650-7661
Number of pages12
JournalJournal of virology
Volume86
Issue number14
DOIs
StatePublished - Jul 1 2012

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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