A big role for small RNAs in influenza virus replication

Scull, Margaret A.; Rice, Charles M.

doi:10.1073/pnas.1006673107

Cited by 9 publications

(6 citation statements)

References 23 publications

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“…Second, no drug-resistant influenza virus could be selected after more than 20 passages of viral propagation under the selection pressure of BPR3P0128 (data not shown). In addition, and most importantly, identifying the target genes of BPR3P0128 could help solve the long-studied problem of the nature of the host factor(s) regulating the switch between transcription and replication by the influenza virus (51). This candidate host factor(s) must fulfill the following criteria.…”

Section: Discussionmentioning

confidence: 99%

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Identification of BPR3P0128 as an Inhibitor of Cap-Snatching Activities of Influenza Virus

Hsu

Yeh

Lin

et al. 2012

Antimicrob Agents Chemother

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The aim of this study was to identify the antiviral mechanism of a novel compound, BPR3P0128. From a large-scale screening of a library of small compounds, BPR3P compounds were found to be potent inhibitors of influenza viral replication in MadinDarby canine kidney (MDCK) cells. BPR3P0128 exhibited inhibitory activity against both influenza A and B viruses. The 50% inhibitory concentrations were in the range of 51 to 190 nM in MDCK cells, as measured by inhibition-of-cytopathic-effect assays. BPR3P0128 appeared to target the viral replication cycle but had no effect on viral adsorption. The inhibition of capdependent mRNA transcription by BPR3P0128 was more prominent with a concurrent increase in cap-independent cRNA replication in a primer extension assay, suggesting a role of BPR3P0128 in switching transcription to replication. This reduction in mRNA expression resulted from the BPR3P-mediated inhibition of the cap-dependent endoribonuclease (cap-snatching) activities of nuclear extracts containing the influenza virus polymerase complex. No inhibition of binding of 5= viral RNA to the viral polymerase complex by this compound was detected. BPR3P0128 also effectively inhibited other RNA viruses, such as enterovirus 71 and human rhinovirus, but not DNA viruses, suggesting that BPR3P0128 targets a cellular factor(s) associated with viral PB2 cap-snatching activity. The identification of this factor(s) could help redefine the regulation of viral transcription and replication and thereby provide a potential target for antiviral chemotherapeutics.

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Section: Discussionmentioning

confidence: 99%

“…Various models of switching from transcription to replication in influenza A viral infections have been proposed (46,51). NP, which is involved in encapsulation of the vRNA, was identified as a key player because of its RNA binding, which might modify the panhandle structure for the switch (17).…”

Section: Discussionmentioning

confidence: 99%

Identification of BPR3P0128 as an Inhibitor of Cap-Snatching Activities of Influenza Virus

Hsu

Yeh

Lin

et al. 2012

Antimicrob Agents Chemother

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“…Transcription of vRNA produces mRNA and complementary RNA (cRNA). The former serve as the template for synthesis of viral proteins, and the latter are templates for synthesis of more vRNA for production of new virions [24]. We next performed RT-qPCR to evaluate the effect of brevilin A on viral RNA synthesis.…”

Section: Resultsmentioning

confidence: 99%

Brevilin A, a Sesquiterpene Lactone, Inhibits the Replication of Influenza A Virus In Vitro and In Vivo

Zhang

Xia

Yang

et al. 2019

Viruses

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With the emergence of drug-resistant strains of influenza A viruses (IAV), new antivirals are needed to supplement the existing counter measures against IAV infection. We have previously shown that brevilin A, a sesquiterpene lactone isolated from C. minima, suppresses the infection of influenza A/PR/8/34 (H1N1) in vitro. Here, we further investigate the antiviral activity and mode of action of brevilin A against different IAV subtypes. Brevilin A inhibited the replication of influenza A H1N1, H3N2, and H9N2 viruses in vitro. The suppression effect of brevilin A was observed as early as 4–8 hours post infection (hpi). Furthermore, we determined that brevilin A inhibited viral replication in three aspects, including viral RNA (vRNA) synthesis, expression of viral mRNA, and protein encoded from the M and NS segments, and nuclear export of viral ribonucleoproteins (vRNPs). The anti-IAV activity of brevilin A was further confirmed in mice. A delayed time-to-death with 50% surviving up to 14 days post infection was obtained with brevilin A (at a dose of 25 mg/kg) treated animals compared to the control cohorts. Together, these results are encouraging for the exploration of sesquiterpene lactones with similar structure to brevilin A as potential anti-influenza therapies.

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“…This molecule can be a host or short viral RNA. Small RNAs are produced during an infection by influenza A (Umbach, Yen, Poon, & Cullen, 2010), which suggests that they determine the change from transcription to replication (Scull & Rice, 2010). These small RNAs may be produced during ISAV infection and at the same time act as support molecules for recombination since they are complementary to parts of the viral genome.…”

Section: Discussionmentioning

confidence: 99%

Rapid sequence modification in the highly polymorphic region (HPR) of the hemagglutinin gene of the infectious salmon anaemia virus (ISAV) suggests intra‐segmental template switching recombination

Cárdenas

Galleguillos

Acevedo

et al. 2020

Journal of Fish Diseases

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The ISAV has a genome composed of eight segments of (–)ssRNA, segment 6 codes for the hemagglutinin–esterase protein, and has the most variable region of the genome, the highly polymorphic region (HPR), which is unique among orthomyxoviruses. The HPR has been associated with virulence, infectivity and pathogenicity. The full length of the HPR is called HPR0 and the strain with this HPR is avirulent, in contrast to strains with deleted HPR that are virulent to varying degrees. The molecular mechanism that gives rise to the different HPRs remains unclear. Here, we studied in vitro the evolution of reassortant recombinant ISAV (rISAV) in Atlantic salmon head kidney (ASK) cells. To this end, we rescued and cultivated a set of rISAV with different segment 6‐HPR genotypes using a reverse genetics system and then sequencing HPR regions of the viruses. Our results show rapid multiple recombination events in ISAV, with sequence insertions and deletions in the HPR, indicating a dynamic process. Inserted sequences can be found in four segments of the ISAV genome (segments 1, 5, 6, and 8). The results suggest intra‐segmental heterologous recombination, probably by class I and class II template switching, similar to the proposed segment 5 recombination mechanism.

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A big role for small RNAs in influenza virus replication

Cited by 9 publications

References 23 publications

Identification of BPR3P0128 as an Inhibitor of Cap-Snatching Activities of Influenza Virus

Identification of BPR3P0128 as an Inhibitor of Cap-Snatching Activities of Influenza Virus

Brevilin A, a Sesquiterpene Lactone, Inhibits the Replication of Influenza A Virus In Vitro and In Vivo

Rapid sequence modification in the highly polymorphic region (HPR) of the hemagglutinin gene of the infectious salmon anaemia virus (ISAV) suggests intra‐segmental template switching recombination

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