Abstract
BackgroundThe genus Nairovirus in the family Bunyaviridae contains 34 tick-borne viruses classified into seven serogroups. Hazara virus (HAZV) belongs to the Crimean-Congo hemorrhagic fever (CCHF) serogroup that also includes CCHF virus (CCHFV) a major pathogen for humans. HAZV is an interesting model to study CCHFV due to a close serological and phylogenetical relationship and a classification which allows handling in a BSL2 laboratory. Nairoviruses are characterized by a tripartite negative-sense single stranded RNA genome (named L, M and S segments) that encode the RNA polymerase, the Gn-Gc glycoproteins and the nucleoprotein (NP), respectively. Currently, there are neither vaccines nor effective therapies for the treatment of any bunyavirus infection in humans. In this study we report, for the first time, the use of RNA interference (RNAi) as an approach to inhibit nairovirus replication.ResultsChemically synthesized siRNAs were designed to target the mRNA produced by the three genomic segments. We first demonstrated that the siRNAs targeting the NP mRNA displayed a stronger antiviral effect than those complementary to the L and M transcripts in A549 cells. We further characterized the two most efficient siRNAs showing, that the induced inhibition is specific and associated with a decrease in NP synthesis during HAZV infection. Furthermore, both siRNAs depicted an antiviral activity when used before and after HAZV infection. We next showed that HAZV was sensitive to ribavirin which is also known to inhibit CCHFV. Finally, we demonstrated the additive or synergistic antiviral effect of siRNAs used in combination with ribavirin.ConclusionsOur study highlights the interest of using RNAi (alone or in combination with ribavirin) to treat nairovirus infection. This approach has to be considered for the development of future antiviral compounds targeting CCHFV, the most pathogenic nairovirus.
Highlights
The genus Nairovirus in the family Bunyaviridae contains 34 tick-borne viruses classified into seven serogroups
We demonstrated that Small interfering RNAs (siRNAs) targeting the NP mRNA depicted a stronger antiviral effect than those designed to inhibit the L and M segment encoded mRNAs. siRNAs were efficient when transfected in cells before or after Hazara virus (HAZV) infection and their use in combination with ribavirin induced a synergistic or an additive antiviral effect, according to the dose of ribavirin used
Inhibition of HAZV replication using segment-specific siRNAs To evaluate the inhibitory activity of siRNAs on HAZV replication, twelve siRNAs were designed to target the mRNAs produced by the L, M, and S genomic segments (Table 1)
Summary
The genus Nairovirus in the family Bunyaviridae contains 34 tick-borne viruses classified into seven serogroups. HAZV is an interesting model to study CCHFV due to a close serological and phylogenetical relationship and a classification which allows handling in a BSL2 laboratory. Nairovirus comprises 34 tick-borne viruses classified into seven serogroups. The main representative serogroups are the Nairobi sheep disease group containing Nairobi sheep disease virus (NSDV) and Dugbe virus and the Crimean-Congo hemorrhagic fever (CCHF) group including HAZV and Crimean-Congo hemorrhagic fever virus (CCHFV) [1,2]. HAZV represents an alternative model to study CCHFV due to its close serological and phylogenetical relationship [13]. It can be handled in BSL2 laboratories
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