20962098
not annotated - annotated - LINNAEUS only
PB2 residue 158 is a pathogenic determinant of pandemic H1N1 and H5 influenza a viruses in mice.
Influenza A viruses are human and animal pathogens that cause morbidity and mortality, which range from mild to severe. The 2009 H1N1 pandemic was caused by the emergence of a reassortant H1N1 subtype (H1N1pdm) influenza A virus containing gene segments that originally circulated in human, avian, and swine virus reservoirs. The molecular determinants of replication and pathogenesis of H1N1pdm viruses in humans and other mammals are poorly understood. Therefore, we set out to elucidate viral determinants critical to the pathogenesis of this novel reassortant using a mouse model. We found that a glutamate-to-glycine substitution at residue 158 of the PB2 gene (PB2-E158G) increased the morbidity and mortality of the parental H1N1pdm virus. Results from mini-genome replication assays in human cells and virus titration in mouse tissues demonstrated that PB2-E158G is a pathogenic determinant, because it significantly increases viral replication rates. The virus load in PB2-E158G-infected mouse lungs was 1,300-fold higher than that of the wild-type virus. Our data also show that PB2-E158G had a much stronger influence on the RNA replication and pathogenesis of H1N1pdm viruses than PB2-E627K, which is a known pathogenic determinant. Remarkably, PB2-E158G substitutions also altered the pathotypes of two avian H5 viruses in mice, indicating that this residue impacts genetically divergent influenza A viruses and suggesting that this region of PB2 could be a new antiviral target. Collectively, the data presented in this study demonstrate that PB2-E158G is a novel pathogenic determinant of influenza A viruses in the mouse model. We speculate that PB2-E158G may be important in the adaptation of avian PB2 genes to other mammals, and BLAST sequence analysis identified a naturally occurring human H1N1pdm isolate that has this substitution. Therefore, future surveillance efforts should include scrutiny of this region of PB2 because of its potential impact on pathogenesis.
Ann file
T1 Species 56 60 H1N1
N1 Reference T1 Taxonomy:11320
T2 Species 65 87 H5 influenza a viruses
N2 Reference T2 Taxonomy:11320
T3 Species 91 95 mice
N3 Reference T3 Taxonomy:10090
T4 Species 99 118 Influenza A viruses
N4 Reference T4 Taxonomy:11320
T5 Species 123 128 human
N5 Reference T5 Taxonomy:9606
T6 Species 228 232 H1N1
N6 Reference T6 Taxonomy:11320
T7 Species 287 291 H1N1
N7 Reference T7 Taxonomy:11320
T8 Species 301 308 H1N1pdm
N8 Reference T8 Taxonomy:11320
T9 Species 310 327 influenza A virus
N9 Reference T9 Taxonomy:11320
T10 Species 383 388 human
N10 Reference T10 Taxonomy:9606
T11 Species 401 406 swine
N11 Reference T11 Taxonomy:9823
T12 Species 487 502 H1N1pdm viruses
N12 Reference T12 Taxonomy:11320
T13 Species 506 512 humans
N13 Reference T13 Taxonomy:9606
T14 Species 671 676 mouse
N14 Reference T14 Taxonomy:10090
T15 Species 831 844 H1N1pdm virus
N15 Reference T15 Taxonomy:11320
T16 Species 893 898 human
N16 Reference T16 Taxonomy:9606
T17 Species 928 933 mouse
N17 Reference T17 Taxonomy:10090
T18 Species 1096 1101 mouse
N18 Reference T18 Taxonomy:10090
T19 Species 1271 1286 H1N1pdm viruses
N19 Reference T19 Taxonomy:11320
T20 Species 1421 1431 H5 viruses
N20 Reference T20 Taxonomy:11320
T21 Species 1435 1439 mice
N21 Reference T21 Taxonomy:10090
T22 Species 1500 1519 influenza A viruses
N22 Reference T22 Taxonomy:11320
T23 Species 1703 1722 influenza A viruses
N23 Reference T23 Taxonomy:11320
T24 Species 1730 1735 mouse
N24 Reference T24 Taxonomy:10090
T25 Species 1904 1909 human
N25 Reference T25 Taxonomy:9606
T26 Species 1910 1917 H1N1pdm
N26 Reference T26 Taxonomy:11320
#1 AnnotatorNotes T25 TODO check span: virus related