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 Tseng, Bin Gong, Shuetsu Fukushi, Shigeru Morikawa, Alexander Freiberg, Tetsuro Ikegami

Research output: Contribution to journalArticle

17 Citations (Scopus)

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 2012

Fingerprint

Rift Valley fever virus
eIF-2 Kinase
Double-Stranded RNA
double-stranded RNA
protein kinases
Vaccines
vaccines
mice
Neutralizing Antibodies
neutralizing antibodies
lymph nodes
Phlebovirus
virulence
Lymph Nodes
Bunyaviridae
biosafety
abortion (animals)
interferon-alpha
Induced Abortion
Viral Antigens

ASJC Scopus subject areas

  • Immunology
  • Virology

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The dominant-negative inhibition of double-stranded RNA-dependent protein kinase PKR increases the efficacy of rift valley fever virus MP-12 vaccine. / Lihoradova, Olga; Kalveram, Birte; Indran, Sabarish V.; Lokugamage, Nandadeva; Juelich, Terry L.; Hill, Terence E.; Tseng, Chien-Te; Gong, Bin; Fukushi, Shuetsu; Morikawa, Shigeru; Freiberg, Alexander; Ikegami, Tetsuro.

In: Journal of Virology, Vol. 86, No. 14, 07.2012, p. 7650-7661.

Research output: Contribution to journalArticle

Lihoradova, Olga ; Kalveram, Birte ; Indran, Sabarish V. ; Lokugamage, Nandadeva ; Juelich, Terry L. ; Hill, Terence E. ; Tseng, Chien-Te ; Gong, Bin ; Fukushi, Shuetsu ; Morikawa, Shigeru ; Freiberg, Alexander ; Ikegami, Tetsuro. / The dominant-negative inhibition of double-stranded RNA-dependent protein kinase PKR increases the efficacy of rift valley fever virus MP-12 vaccine. In: Journal of Virology. 2012 ; Vol. 86, No. 14. pp. 7650-7661.
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