Inhibition of influenza A virus replication by influenza B virus nucleoprotein: An insight into interference between influenza A and B viruses

Wanitchang, Asawin; Narkpuk, Jaraspim; Jaru-Ampornpan, Peera; Jengarn, Juggragarn; Jongkaewwattana, Anan

doi:10.1016/j.virol.2012.06.016

Cited by 26 publications

(25 citation statements)

References 41 publications

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“…4) (21, 78). However, our and previous results indicate that the NP of influenza B virus inhibits type A RdRp activity (56). This mechanism could clearly account for the lack of segment reassortment between influenza A and B viruses but does not explain why influenza A viruses carrying influenza B virus segments in the absence of influenza B virus NP cannot be generated.…”

Section: Discussioncontrasting

confidence: 76%

See 1 more Smart Citation

Influenza A and B Virus Intertypic Reassortment through Compatible Viral Packaging Signals

Baker

Nogales

Finch

et al. 2014

J Virol

104

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Influenza A and B viruses cocirculate in humans and together cause disease and seasonal epidemics. These two types of influenza viruses are evolutionarily divergent, and exchange of genetic segments inside coinfected cells occurs frequently within types but never between influenza A and B viruses. Possible mechanisms inhibiting the intertypic reassortment of genetic segments could be due to incompatible protein functions of segment homologs, a lack of processing of heterotypic segments by influenza virus RNA-dependent RNA polymerase, an inhibitory effect of viral proteins on heterotypic virus function, or an inability to specifically incorporate heterotypic segments into budding virions. Here, we demonstrate that the full-length hemagglutinin (HA) of prototype influenza B viruses can complement the function of multiple influenza A viruses. We show that viral noncoding regions were sufficient to drive gene expression for either type A or B influenza virus with its cognate or heterotypic polymerase. The native influenza B virus HA segment could not be incorporated into influenza A virus virions. However, by adding the influenza A virus packaging signals to full-length influenza B virus glycoproteins, we rescued influenza A viruses that possessed HA, NA, or both HA and NA of influenza B virus. Furthermore, we show that, similar to single-cycle infectious influenza A virus, influenza B virus cannot incorporate heterotypic transgenes due to packaging signal incompatibilities. Altogether, these results demonstrate that the lack of influenza A and B virus reassortants can be attributed at least in part to incompatibilities in the virus-specific packaging signals required for effective segment incorporation into nascent virions. IMPORTANCEReassortment of influenza A or B viruses provides an evolutionary strategy leading to unique genotypes, which can spawn influenza A viruses with pandemic potential. However, the mechanism preventing intertypic reassortment or gene exchange between influenza A and B viruses is not well understood. Nucleotides comprising the coding termini of each influenza A virus gene segment are required for specific segment incorporation during budding. Whether influenza B virus shares a similar selective packaging strategy or if packaging signals prevent intertypic reassortment remains unknown. Here, we provide evidence suggesting a similar mechanism of influenza B virus genome packaging. Furthermore, by appending influenza A virus packaging signals onto influenza B virus segments, we rescued recombinant influenza A/B viruses that could reassort in vitro with another influenza A virus. These findings suggest that the divergent evolution of packaging signals aids with the speciation of influenza A and B viruses and is in part responsible for the lack of intertypic viral reassortment.

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Section: Discussioncontrasting

confidence: 76%

“…Other discrepancies that might impede heterotypic reassortment could include the inhibitory effect of influenza B virus NP on influenza A virus replication (56). Indeed, we observed that coexpression of influenza B virus NP inhibited IAV MG expression, whereas that of the NP of another negative-stranded RNA virus (LCMV) did not (Fig.…”

Section: Resultsmentioning

confidence: 81%

Influenza A and B Virus Intertypic Reassortment through Compatible Viral Packaging Signals

Baker

Nogales

Finch

et al. 2014

J Virol

104

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“…Reporter-expressing sciIAVs ΔNA were developed as vaccine candidates (Shinya et al, 2004), to evaluate viral attachment to the host cell (Rimmelzwaan et al, 2007), rate of co-infections (Bodewes et al, 2012), as a tool for NAb screening (Rimmelzwaan et al, 2011), or for inhibition during intertypic infection (Wanitchang et al, 2012). Although recombinant sciIAV lacking NA enzymatic activity has similar growth kinetics as WT virus in the presence of exogenous Vibrio cholerae sialidase, sciIAV ΔNA grows with reduced replication levels compared with WT virus lacking enzyme supplementation, thus it can be considered a pseudo-sciIAV (our unpublished results) (Fujii et al, 2003; Inagaki et al, 2012).…”

Section: Single-cycle Infectious Influenza a Viruses (Sciiav)mentioning

confidence: 99%

Development and applications of single-cycle infectious influenza A virus (sciIAV)

et al. 2016

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The diverse host range, high transmissibility, and rapid evolution of influenza A viruses justify the importance of containing pathogenic viruses studied in the laboratory. Other than physically or mechanically changing influenza A virus containment procedures, modifying the virus to only replicate for a single round of infection similarly ensures safety and consequently decreases the level of biosafety containment required to study highly pathogenic members in the virus family. This biological containment is more ideal because it is less apt to computer, machine, or human error. With many necessary proteins that can be deleted, generation of single-cycle infectious influenza A viruses (sciIAV) can be achieved using a variety of approaches. Here, we review the recent burst in sciIAV generation and summarize the applications and findings on this important human pathogen using biocontained viral mimics.

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“…There are contradicting reports concerning the role of the N-terminal region of BNP in terms of its effect on BNP cellular distribution and the effect this likely has on the ability of BNP to support transcription and replication of a virus-like RNA (14,24,25). None of the previous studies were performed in the context of viral infection but by using protein expression methods in which intracellular conditions are significantly different from those during infection (27,28).…”

Section: Discussionmentioning

confidence: 99%

“…Previous work reported that this N-terminal extension is not essential for nuclear accumulation of BNP or for the protein to function in an in vitro transcription/replication assay (14). More recent studies have reported conflicting evidence demonstrating that multiple regions of the N-terminal extension are required for efficient nuclear import of BNP (24,25).…”

mentioning

confidence: 99%

The N Terminus of the Influenza B Virus Nucleoprotein Is Essential for Virus Viability, Nuclear Localization, and Optimal Transcription and Replication of the Viral Genome

Sherry

Smith

Davidson

et al. 2014

J Virol

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The nucleoprotein (NP) of influenza viruses is a multifunctional protein with essential roles throughout viral replication. Despite influenza A and B viruses belonging to separate genera of the Orthomyxoviridae family, their NP proteins share a relatively high level of sequence conservation. However, NP of influenza B viruses (BNP) contains an evolutionarily conserved N-terminal 50-amino-acid extension that is absent from NP of influenza A viruses. There is conflicting evidence as to the functions of the BNP N-terminal extension; however, this has never been assessed in the context of viral infection. We have used reverse genetics to assess the significance of this region on the functions of BNP and virus viability. The truncation of more than three amino acids prevented virus recovery, suggesting that the N-terminal extension is essential for virus viability. Mutational analysis indicated that multiple regions of the protein are involved in the nuclear localization of BNP, with the entire N-terminal extension required for this to function efficiently. Viruses containing mutations in the first 10 residues of BNP demonstrated few differences in nuclear localization; however, the viruses exhibited significant reductions in viral mRNA transcription and genome replication, resulting in significantly attenuated phenotypes. Mutations introduced to ablate a previously reported nuclear localization signal also resulted in a significant decrease in mRNA production during early stages of viral replication. Overall, our results demonstrate that the N-terminal extension of BNP is essential to virus viability not only for directing nuclear localization of BNP but also for regulating viral mRNA transcription and genome replication. IMPORTANCEThe multifunctional NP of influenza viruses has roles throughout the viral replication cycle; therefore, it is essential for virus viability. Despite high levels of homology between the NP of influenza A and B viruses, the NP of influenza B virus contains an evolutionarily conserved 50-amino-acid N-terminal extension that is absent from the NP of influenza A viruses. In this study, we show that this N-terminal extension is essential for virus viability, and we confirm and expand upon recent findings that this region of BNP is required for nuclear localization of the protein. Furthermore, we demonstrate for the first time that the N terminus of BNP is involved in regulating viral mRNA transcription and replication of the viral genome. As the NP of influenza A virus lacks this N-terminal extension, these viruses may have evolved separate mechanisms to regulate these processes.

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Inhibition of influenza A virus replication by influenza B virus nucleoprotein: An insight into interference between influenza A and B viruses

Cited by 26 publications

References 41 publications

Influenza A and B Virus Intertypic Reassortment through Compatible Viral Packaging Signals

Influenza A and B Virus Intertypic Reassortment through Compatible Viral Packaging Signals

Development and applications of single-cycle infectious influenza A virus (sciIAV)

The N Terminus of the Influenza B Virus Nucleoprotein Is Essential for Virus Viability, Nuclear Localization, and Optimal Transcription and Replication of the Viral Genome

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