Evolution and Virulence of Influenza A Virus Protein PB1-F2
Identifieur interne : 000D80 ( Pmc/Curation ); précédent : 000D79; suivant : 000D81Evolution and Virulence of Influenza A Virus Protein PB1-F2
Auteurs : Ram P. Kamal [États-Unis] ; Irina V. Alymova ; Ian A. YorkSource :
- International Journal of Molecular Sciences [ 1422-0067 ] ; 2017.
Abstract
PB1-F2 is an accessory protein of most human, avian, swine, equine, and canine influenza A viruses (IAVs). Although it is dispensable for virus replication and growth, it plays significant roles in pathogenesis by interfering with the host innate immune response, inducing death in immune and epithelial cells, altering inflammatory responses, and promoting secondary bacterial pneumonia. The effects of PB1-F2 differ between virus strains and host species. This can at least partially be explained by the presence of multiple PB1-F2 sequence variants, including premature stop codons that lead to the expression of truncated PB1-F2 proteins of different lengths and specific virulence-associated residues that enhance susceptibility to bacterial superinfection. Although there has been a tendency for human seasonal IAV to gradually reduce the number of virulence-associated residues, zoonotic IAVs contain a reservoir of PB1-F2 proteins with full length, virulence-associated sequences. Here, we review the molecular mechanisms by which PB1-F2 may affect influenza virulence, and factors associated with the evolution and selection of this protein.
Url:
DOI: 10.3390/ijms19010096
PubMed: 29286299
PubMed Central: 5796046
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<front><div type="abstract" xml:lang="en"><p>PB1-F2 is an accessory protein of most human, avian, swine, equine, and canine influenza A viruses (IAVs). Although it is dispensable for virus replication and growth, it plays significant roles in pathogenesis by interfering with the host innate immune response, inducing death in immune and epithelial cells, altering inflammatory responses, and promoting secondary bacterial pneumonia. The effects of PB1-F2 differ between virus strains and host species. This can at least partially be explained by the presence of multiple PB1-F2 sequence variants, including premature stop codons that lead to the expression of truncated PB1-F2 proteins of different lengths and specific virulence-associated residues that enhance susceptibility to bacterial superinfection. Although there has been a tendency for human seasonal IAV to gradually reduce the number of virulence-associated residues, zoonotic IAVs contain a reservoir of PB1-F2 proteins with full length, virulence-associated sequences. Here, we review the molecular mechanisms by which PB1-F2 may affect influenza virulence, and factors associated with the evolution and selection of this protein.</p>
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<pmc article-type="review-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Int J Mol Sci</journal-id>
<journal-id journal-id-type="iso-abbrev">Int J Mol Sci</journal-id>
<journal-id journal-id-type="publisher-id">ijms</journal-id>
<journal-title-group><journal-title>International Journal of Molecular Sciences</journal-title>
</journal-title-group>
<issn pub-type="epub">1422-0067</issn>
<publisher><publisher-name>MDPI</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">29286299</article-id>
<article-id pub-id-type="pmc">5796046</article-id>
<article-id pub-id-type="doi">10.3390/ijms19010096</article-id>
<article-id pub-id-type="publisher-id">ijms-19-00096</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Review</subject>
</subj-group>
</article-categories>
<title-group><article-title>Evolution and Virulence of Influenza A Virus Protein PB1-F2</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Kamal</surname>
<given-names>Ram P.</given-names>
</name>
<xref ref-type="aff" rid="af1-ijms-19-00096">1</xref>
<xref ref-type="aff" rid="af2-ijms-19-00096">2</xref>
<xref rid="c1-ijms-19-00096" ref-type="corresp">*</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Alymova</surname>
<given-names>Irina V.</given-names>
</name>
<xref ref-type="aff" rid="af2-ijms-19-00096">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>York</surname>
<given-names>Ian A.</given-names>
</name>
<xref ref-type="aff" rid="af2-ijms-19-00096">2</xref>
</contrib>
</contrib-group>
<aff id="af1-ijms-19-00096"><label>1</label>
Battelle Memorial Institute, Atlanta, GA 30329, USA</aff>
<aff id="af2-ijms-19-00096"><label>2</label>
Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA;<email>xeq3@cdc.gov</email>
(I.V.A.);<email>ite1@cdc.gov</email>
(I.A.Y.)</aff>
<author-notes><corresp id="c1-ijms-19-00096"><label>*</label>
Correspondence: <email>keu7@cdc.gov</email>
; Tel.: +1-404-639-4487</corresp>
</author-notes>
<pub-date pub-type="epub"><day>29</day>
<month>12</month>
<year>2017</year>
</pub-date>
<pub-date pub-type="collection"><month>1</month>
<year>2018</year>
</pub-date>
<volume>19</volume>
<issue>1</issue>
<elocation-id>96</elocation-id>
<history><date date-type="received"><day>24</day>
<month>11</month>
<year>2017</year>
</date>
<date date-type="accepted"><day>25</day>
<month>12</month>
<year>2017</year>
</date>
</history>
<permissions><copyright-statement>© 2017 by the authors.</copyright-statement>
<copyright-year>2017</copyright-year>
<license license-type="open-access"><license-p>Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>
).</license-p>
</license>
</permissions>
<abstract><p>PB1-F2 is an accessory protein of most human, avian, swine, equine, and canine influenza A viruses (IAVs). Although it is dispensable for virus replication and growth, it plays significant roles in pathogenesis by interfering with the host innate immune response, inducing death in immune and epithelial cells, altering inflammatory responses, and promoting secondary bacterial pneumonia. The effects of PB1-F2 differ between virus strains and host species. This can at least partially be explained by the presence of multiple PB1-F2 sequence variants, including premature stop codons that lead to the expression of truncated PB1-F2 proteins of different lengths and specific virulence-associated residues that enhance susceptibility to bacterial superinfection. Although there has been a tendency for human seasonal IAV to gradually reduce the number of virulence-associated residues, zoonotic IAVs contain a reservoir of PB1-F2 proteins with full length, virulence-associated sequences. Here, we review the molecular mechanisms by which PB1-F2 may affect influenza virulence, and factors associated with the evolution and selection of this protein.</p>
</abstract>
<kwd-group><kwd>influenza</kwd>
<kwd>PB1-F2</kwd>
<kwd>virulence</kwd>
<kwd>pathogenesis</kwd>
</kwd-group>
</article-meta>
</front>
<floats-group><fig id="ijms-19-00096-f001" orientation="portrait" position="float"><label>Figure 1</label>
<caption><p>Secondary structure of PB1-F2 C-terminus differ between highly and less virulent viruses. (Adapted from Solbak et al., 2013 [<xref rid="B16-ijms-19-00096" ref-type="bibr">16</xref>
]). The overall predicted secondary structures of full-length PB1-F2 of PR8, 2009pdmH1N1 *, 1918 H1N1 and HPAIV H5N1 are shown. Regions with the best-defined α-helical structure in the C-terminal are denoted with broad cylinders, whereas regions with lesser-defined α-helical structure in the N-terminals appear as thin cylinders. PB1-F2 of less virulent strains have one longer α-helix, while the highly virulent viruses contain two α-helices in its C-terminus. The positions and residues of virulent sequence variants of PB1-F2 are shown in green (N66S), blue (the cytotoxic motif), and red (the inflammatory motif). * All 2009pdmH1N1 express PB1-F2 of only 11 amino acids. The structure shown was predicted for full-length PB1-F2, restored by mutating pre-mature stops codons.</p>
</caption>
<graphic xlink:href="ijms-19-00096-g001"></graphic>
</fig>
<fig id="ijms-19-00096-f002" orientation="portrait" position="float"><label>Figure 2</label>
<caption><p>Signature positions on PB1-F2 protein. The amino acid sequence of PR8 PB1-F2 is shown. The significant positions of interest found in PB1-F2 of all IAVs are marked irrespective of their presence in PR8 PB1-F2. PB1-F2 ORF has three in-frame downstream translation initiation sites (<bold>highlighted green</bold>
). Many IAV isolates express truncated PB1-F2 due to the presence of premature stop codon(s) (<bold>highlighted blue</bold>
). Three major sequence variants of PB1-F2 i.e., N66S (<bold>highlighted yellow</bold>
), cytotoxic motif (<bold>highlighted red</bold>
) and inflammatory motif (<bold>highlighted red</bold>
) have been associated with enhanced virulence.</p>
</caption>
<graphic xlink:href="ijms-19-00096-g002"></graphic>
</fig>
<fig id="ijms-19-00096-f003" orientation="portrait" position="float"><label>Figure 3</label>
<caption><p>Molecular mechanisms of PB1-F2 virulence. Right side of the diagram shows an IAV infected cell; left side shows a macrophage phagocytosing virus-infected cells. (<bold>Right</bold>
) Upon IAV infection, viral RNA is discovered by TLRs in endosomes and RIG-I and MDA5 in the cytosol. RIG-I and/or MDA5 triggers MAVS-mediated activation of the innate immune response. MAVS recruits TRAF3 and TRAF6. TRAF3 leads to production of Type I IFNs through IRF3 and IRF7 pathways. TRAF6, through NF-κB, stimulates expression of inflammatory cytokines. PB1-F2 inhibits type I IFNs by interfering with MAVS, TBK1 and IRF3 (A). PB1-F2 localized to mitochondria leads to loss of mitochondrial outer membrane potential (MOMP) (B) either by binding to mitochondrial membrane proteins VDAC and ANT3, activation of BAK/BAX, or pore forming through PB1-F2 oligomerization. MOMP loss releases cytochrome <italic>c</italic>
into the cytosol, activates caspase cascades, and leads to apoptosis. By binding to CALCOCO2 (C), PB1-F2 inhibits IFN signaling pathway, but also stimulates TRAF6-mediated NF-κB activation, thus promoting inflammatory cytokine production (D). (<bold>Left</bold>
) PB1-F2 stimulates NLRP3 inflammasomes in macrophages upon phagocytosis of virus-infected dead cells (E). Inflammasome activation leads to maturation and release of IL-1β and IL-18.</p>
</caption>
<graphic xlink:href="ijms-19-00096-g003"></graphic>
</fig>
<table-wrap id="ijms-19-00096-t001" orientation="portrait" position="float"><object-id pub-id-type="pii">ijms-19-00096-t001_Table 1</object-id>
<label>Table 1</label>
<caption><p>Common length and virulent sequence variants of IAV PB1-F2.</p>
</caption>
<table frame="hsides" rules="groups"><thead><tr><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Host</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">IAV Subtype</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">% of Isolates with Full Length Protein (≥90aa)</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Common Length Variants (% of Isolates)</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Common Virulent Residues in Isolates Expressing PB1-F2 ≥62aa</th>
</tr>
</thead>
<tbody><tr><td rowspan="12" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Human</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1918pdmH1N1</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">100</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">N/A</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Complete inflammatory motif with 66S and 70V</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Seasonal H1N1</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><1</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">57aa (96.8)</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">2009pdmH1N1</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">11aa (100)</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">H1N1 SOIV <sup>a</sup>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">57</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">11aa (14.3)<break></break>
57aa (14.3)<break></break>
79aa (14.3)</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">100% have 2 inflammatory residues (62L and 82L).</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">H1N2</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">100</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">N/A</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">No significant prevalence</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">H1N2 SOIV <sup>a</sup>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">50</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">11aa (25)</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">100% have 2 inflammatory residues (62L and 82L).</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">H2N2</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">>98</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">N/A</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Majority have complete inflammatory motif.</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Seasonal H3N2</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">91.3</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">34aa (6.7)</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Majority have 1 cytotoxic residue (70V). 10% of recent (2015–2017) isolates have 70V and 79R.</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">H3N2 SOIV <sup>a</sup>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">>99</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">N/A</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Majority have 2 inflammatory residues (62L and 82L)</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">H5N1 <sup>b</sup>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">94</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">23aa (3)</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Majority have complete inflammatory motif.</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">H5N6 <sup>b</sup>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">66</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">57aa (27)</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">50% have complete inflammatory motif.</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">H7N9 <sup>b</sup>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">86</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">57aa (5)</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Majority have complete inflammatory motif.</td>
</tr>
<tr><td rowspan="3" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Swine</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">H1N1</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">42</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">11aa (29), 79aa (19)</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">28.6% have complete inflammatory motif.</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">H1N2</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">82</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">79aa (5.7), 57aa (5)</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">6.4% have complete inflammatory motif. Majority have 2 inflammatory residues (62L and 82L)</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">H3N2</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">79</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">79aa (12), 35aa (3)</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">2.4% have complete inflammatory motif. Majority have 2 inflammatory residues (62L and 82L)</td>
</tr>
<tr><td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Equine</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">H3N8</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">50</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">81aa (50)</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">85% have 3 inflammatory residues.</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">H7N7</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">75</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">34aa (25)</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">100% have 3 inflammatory residues.</td>
</tr>
<tr><td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Canine</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">H3N2</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">94.7</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">12aa (5.3)</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">100% have 3 inflammatory residues.</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">H3N8</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">65.1</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">24aa (34.9)</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">22% have complete inflammatory motif.</td>
</tr>
<tr><td rowspan="3" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">Avian</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">H5N1</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">88.3</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">57aa (7.6), 24/25aa (2.03)</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Majority have complete inflammatory motif.</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">H7N9</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">83</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">25aa (6), 34aa (5)</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Majority have complete inflammatory motif.</td>
</tr>
<tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">H9N2</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">81.6</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">79aa (12), 57 (6.4)</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">50% have complete inflammatory motif.</td>
</tr>
</tbody>
</table>
<table-wrap-foot><fn><p>Data are derived from analyses of PB1 sequences retrieved from GISAID and IRD databases as described in (Alymova et al., 2017 [<xref rid="B59-ijms-19-00096" ref-type="bibr">59</xref>
]). <sup>a</sup>
SOIV indicates swine origin influenza viruses isolated from human infections. <sup>b</sup>
Avian influenza viruses infecting humans.</p>
</fn>
</table-wrap-foot>
</table-wrap>
</floats-group>
</pmc>
</record>
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