Full Factorial Analysis of Mammalian and Avian Influenza Polymerase Subunits Suggests a Role of an Efficient Polymerase for Virus Adaptation

Li, Olive T. W.; Chan, Michael C. W.; Leung, Cynthia Sau-Wai; Chan, Renee W. Y.; Guan, Yi; Nicholls, John M.; Poon, Leo L. M.

doi:10.1371/journal.pone.0005658

Cited by 59 publications

(63 citation statements)

References 86 publications

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“…Briefly, the PB2, PB1, PA, and NP cDNAs of a highly pathogenic H5N1 virus, A/Vietnam/1203/04, were synthesized by reverse transcription of viral RNA and subcloned into the pHW2000 vector as described (27). In the RNP assay, pPOLI-NS-Luc was the reporter plasmid used for the determination of the viral polymerase activity (20). Expression of vRNA-like negative-sense luciferase RNA was driven by the polymerase I promoter.…”

Section: Methodsmentioning

confidence: 99%

“…The plasmid pPOLI-NS-Luc that expresses vRNA-like luciferase RNA was used to monitor the activity of viral polymerases. If the RNP is functional, the vRNA produced from the pPOLI-NS-Luc plasmid will be transcribed by the viral polymerases leading to the synthesis of the luciferase protein used as a reporter (20). Human TLR10 expression plasmid was also cotransfected into 293T cells to examine the effect of its expression on viral replication as reflected in the luciferase activity.…”

Section: Tlr10 Is Expressed In Human Macrophages and Its Expression Ismentioning

confidence: 99%

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Toll-like receptor 10 is involved in induction of innate immune responses to influenza virus infection

Lee

Kok

Jaume

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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157

128

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Toll-like receptors (TLRs) play key roles in innate immune recognition of pathogen-associated molecular patterns of invading microbes. Among the 10 TLR family members identified in humans, TLR10 remains an orphan receptor without known agonist or function. TLR10 is a pseudogene in mice and mouse models are noninformative in this regard. Using influenza virus infection in primary human peripheral blood monocyte-derived macrophages and a human monocytic cell line, we now provide previously unidentified evidence that TLR10 plays a role in innate immune responses following viral infection. Influenza virus infection increased TLR10 expression and TLR10 contributed to innate immune sensing of viral infection leading to cytokine induction, including proinflammatory cytokines and interferons. TLR10 induction is more pronounced following infection with highly pathogenic avian influenza H5N1 virus compared with a low pathogenic H1N1 virus. Induction of TLR10 by virus infection requires active virus replication and de novo protein synthesis. Culture supernatants of virus-infected cells modestly up-regulate TLR10 expression in nonvirus-infected cells. Signaling via TLR10 was activated by the functional RNA–protein complex of influenza virus leading to robust induction of cytokine expression. Taken together, our findings identify TLR10 as an important innate immune sensor of viral infection and its role in innate immune defense and immunopathology following viral and bacterial pathogens deserves attention.

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Section: Methodsmentioning

confidence: 99%

Section: Tlr10 Is Expressed In Human Macrophages and Its Expression Ismentioning

confidence: 99%

Toll-like receptor 10 is involved in induction of innate immune responses to influenza virus infection

Lee

Kok

Jaume

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

157

128

View full text Add to dashboard Cite

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“…Plasmids pCIPA, pCIPB1, and pCIPB2 expressing RNA polymerase subunits of influenza B/Panama/45/90 virus were described previously (15). Plasmid pPolI-Luc-RT for the generation of pPol-Luci-BNA-RT and pEGFP were kindly provided by L. L. M. Poon of the University of Hong Kong (18). The pPol-Luci-BNA-RT transcribes a viral RNA (vRNA)-like RNA, in which the noncoding sequences of influenza B NA segment flank the coding region of firefly luciferase.…”

Section: Methodsmentioning

confidence: 99%

Structural Basis for RNA Binding and Homo-Oligomer Formation by Influenza B Virus Nucleoprotein

Lam

Zhang

et al. 2012

J Virol

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Influenza virus nucleoprotein (NP) is the major component of the viral ribonucleoprotein complex, which is crucial for the transcription and replication of the viral genome. We have determined the crystal structure of influenza B virus NP to a resolution of 3.2 Å. Influenza B NP contains a head, a body domain, and a tail loop. The electropositive groove between the head and body domains of influenza B NP is crucial for RNA binding. This groove also contains an extended flexible charged loop (amino acids [aa] 125 to 149), and two lysine clusters at the first half of this loop were shown to be crucial for binding RNA. Influenza B virus NP forms a crystallographic homotetramer by inserting the tail loop into the body domain of the neighboring NP molecule. A deeply buried salt bridge between R472 and E395 and a hydrophobic cluster at F468 are the major driving forces for the insertion. The analysis of the influenza B virus NP structure and function and comparisons with influenza A virus NP provide insights into the mechanisms of action and underpin efforts to design inhibitors for this class of proteins.

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“…Several pieces of evidence argue in favor of the selective advantage hypothesis. First, studies on the compatibility of polymerase proteins from human and avian influenza viruses showed that replacement of the human PB1 by its avian counterpart can enhance polymerase activity in minigenome reporter assays (13)(14)(15). Second, analyses of single-gene reassortants demonstrated an important role of the PB1 segment for the high virulence of the pandemic H1N1/1918 virus in mice and ferrets (16,17).…”

mentioning

confidence: 99%

The Avian-Origin PB1 Gene Segment Facilitated Replication and Transmissibility of the H3N2/1968 Pandemic Influenza Virus

Wendel

Rubbenstroth

Doedt

et al. 2015

J Virol

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IMPORTANCEDespite the high impact of influenza pandemics on human health, some mechanisms underlying the emergence of pandemic influenza viruses still are poorly understood. Thus, it was unclear why both H2N2/1957 and H3N2/1968 reassortant pandemic viruses contained, in addition to the avian HA, the PB1 gene segment of the avian parent. Here, we addressed this long-standing question by modeling the emergence of the H3N2/1968 virus from its putative human and avian precursors. We show that the avian PB1 segment increased activity of the viral polymerase and facilitated viral replication. Our results suggest that in addition to the acquisition of antigenically novel HA (i.e., antigenic shift), enhanced viral polymerase activity is required for the emergence of pandemic influenza viruses from their seasonal human precursors. Influenza A viruses are single-stranded negative-sense RNA viruses. Their genome consists of 8 RNA segments, each of which encodes 1 to 3 proteins (1). Pandemic influenza has been occurring at irregular intervals for at least 500 years, causing significant, occasionally catastrophic mortality in the human population (2, 3). Genetic data available for the last four pandemic viruses (H1N1/1918, H2N2/1957, H3N2/1968, and H1N1/2009) indicate that they all contained an antigenically novel hemagglutinin (HA) which was derived from animal influenza A viruses (reviewed in references 2-5). The origin of the other seven gene segments of the pandemic viruses varied (3,4,6). The source of the non-HA gene segments of the H1N1/1918 virus is not clear due to the lack of sequence data for coexistent avian and mammalian influenza A viruses. The precursor of the H1N1/2009 virus emerged and circulated in pigs; this virus was transmitted and adapted to humans as a whole. Two other pandemic viruses emerged via gene mixing (reassortment) between animal viruses and contemporary human viruses and contained either 5 gene segments (H2N2/1957) or 6 gene segments (H3N2/1968) of the human virus parent.Avian influenza viruses do not replicate efficiently in humans. It is believed that exchange via reassortment of nonadapted gene segments from an avian virus by segments from a human-adapted parent might allow the emerging pandemic virus to overcome host range restriction (2,7,8). Surprisingly, both 1957 and 1968 pandemic viruses contained the avian PB1 segment (gene segment 2) (9). This segment encodes three proteins, polymerase basic protein 1 (PB1), PB1-F2, and PB1-N40, which are translated from the start codons 1, 4, and 5, respectively (1, 10). PB1 is the core subunit of the trimeric viral RNA-dependent RNA polymerase complex (PB1, PB2, and PA), which is responsible for transcription and replication of the viral genome (1, 11). PB1-F2 and PB1-N40 are not essential for virus replication, but they can affect replication efficiency and contribute to pathogenicity (10, 12).

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Full Factorial Analysis of Mammalian and Avian Influenza Polymerase Subunits Suggests a Role of an Efficient Polymerase for Virus Adaptation

Cited by 59 publications

References 86 publications

Toll-like receptor 10 is involved in induction of innate immune responses to influenza virus infection

Toll-like receptor 10 is involved in induction of innate immune responses to influenza virus infection

Structural Basis for RNA Binding and Homo-Oligomer Formation by Influenza B Virus Nucleoprotein

The Avian-Origin PB1 Gene Segment Facilitated Replication and Transmissibility of the H3N2/1968 Pandemic Influenza Virus

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