Multiple polymerase gene mutations for human adaptation occurring in Asian H5N1 influenza virus clinical isolates

Arai, Yasuha; Kawashita, Norihito; Hotta, Kozue; Hoang, Phuong Vu Mai; Nguyen, Hang Le Khanh; Nguyen, Thach Co; Vuong, Cuong Duc; Le, Thanh Thi; Le, Mai Thi Quynh; Soda, Kosuke; Ibrahim, Madiha S.; Daidoji, Tomo; Takagi, Tatsuya; Shioda, Tatsuo; Nakaya, Takaaki; Ito, Toshihiro; Hasebe, Futoshi; Watanabe, Yohei

doi:10.1038/s41598-018-31397-3

Cited by 20 publications

(30 citation statements)

References 52 publications

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“…These results demonstrate a synergistic between sites within a single protein and sites in different proteins; in other words, the polygenic nature of IAV virulence in mice. This is consistent with the observations from various experimental studies, such as the ones that demonstrate intra-protein synergy in PB2 [32–37], PA [15], and NS1 [38, 39], and inter-protein synergy that involves combinations of PB2, PB1, PA, HA or NA [16, 40-46].…”

Section: Discussionsupporting

confidence: 92%

“…The critical role of PB2 in determining virulence in mice have been indeed highlighted for various strains, including H3N2 [44, 47], H5N1 [32-34, 48, 49], H5N8 [36, 50], H7N9 [51–55], H9N2 [35, 37, 55, 56] and H10N8 [55]. Among the top 20 sites in PB2 for PART models, sites 627 and 701 have been repeatedly shown to affect IAV virulence in mammals including mice.…”

Section: Discussionmentioning

confidence: 99%

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Rule-based meta-analysis reveals the major role of PB2 in influencing influenza A virus virulence in mice

Ivan

Kwoh

2019

Preprint

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7Background: Influenza A virus (IAV) poses threats to human health and life. Many individual 8 studies have been carried out in mice to uncover the viral factors responsible for the virulence 9 of IAV infections. Virus adaptation through serial lung-to-lung passaging and reverse genetic 10 engineering and mutagenesis approaches have been widely used in the studies. Nonetheless, a 11 single study may not provide enough confident about virulence factors, hence combining 12 several studies for a meta-analysis is desired to provide better views. 13 Methods: Virulence information of IAV infections and the corresponding virus and mouse 14 strains were documented from literature. Using the mouse lethal dose 50, time series of weight 15 loss or percentage of survival, the virulence of the infections was classified as avirulent or 16 virulent for two-class problems, and as low, intermediate or high for three-class problems. On 17 the other hand, protein sequences were decoded from the corresponding IAV genomes or 18 reconstructed manually from other proteins according to mutations mentioned in the related 19literature. IAV virulence models were then learned from various datasets containing IAV 20 proteins whose amino acids at their aligned position and the corresponding two-class or three-21 class virulence labels. Three proven rule-based learning approaches, i.e., OneR, JRip and 22 PART, and additionally random forest were used for modelling, and top protein sites and 23 synergy between protein sites were identified from the models. 24Results: More than 500 records of IAV infections in mice whose viral proteins could be 25 retrieved were documented. The BALB/C and C57BL/6 mouse strains and the H1N1, H3N2 26 and H5N1 viruses dominated the infection records. PART models learned from full or subsets 27 of datasets achieved the best performance, with moderate averaged model accuracies ranged 28 from 65.0% to 84.4% and from 54.0% to 66.6% for two-class and three-class datasets that 29 utilized all records of aligned IAV proteins, respectively. Their averaged accuracies were 30 comparable or even better than the averaged accuracies of random forest models and should be 31 preferred based on the Occam's razor principle. Interestingly, models based on a dataset that 32 included all IAV strains achieved a better averaged accuracy when host information was taken 33 into account. For model interpretation, we observed that although many sites in HA were highly 34 correlated with virulence, PART models based on sites in PB2 could compete against and were 35 often better than PART models based on sites in HA. Moreover, PART had a high preference 36 to include sites in PB2 when models were learned from datasets containing concatenated 37 alignments of all IAV proteins. Several sites with a known contribution to virulence were found 38 as the top protein sites, and site pairs that may synergistically influence virulence were also 39 uncovered. 40 Conclusion: Modelling the virulence of IAV infections is a challenging problem. Rule-bas...

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Rule-based meta-analysis reveals the major role of PB2 in influencing influenza A virus virulence in mice

Ivan

Kwoh

2019

Preprint

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“…However, detailed analysis of H5N1 viruses also revealed the presence of host adaptive mutations in PA. In particular, this includes mutations at residues A343T and N383D that activate polymerase activity in human cells in the absence of PB2 E627K or D701N [24,48]. In addition to these experimentally confirmed adaptive mutations in PA, some bioinformatics analysis suggest that there are additional residues involved in mammalian host adaptation [49][50][51][52].…”

Section: Contribution Of Mutations In Pa To Host Adaptationmentioning

confidence: 99%

Key Role of the Influenza A Virus PA Gene Segment in the Emergence of Pandemic Viruses

Lutz

Dunagan

Kurebayashi

et al. 2020

Viruses

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Influenza A viruses (IAVs) are a significant human pathogen that cause seasonal epidemics and occasional pandemics. Avian waterfowl are the natural reservoir of IAVs, but a wide range of species can serve as hosts. Most IAV strains are adapted to one host species and avian strains of IAV replicate poorly in most mammalian hosts. Importantly, IAV polymerases from avian strains function poorly in mammalian cells but host adaptive mutations can restore activity. The 2009 pandemic H1N1 (H1N1pdm09) virus acquired multiple mutations in the PA gene that activated polymerase activity in mammalian cells, even in the absence of previously identified host adaptive mutations in other polymerase genes. These mutations in PA localize within different regions of the protein suggesting multiple mechanisms exist to activate polymerase activity. Additionally, an immunomodulatory protein, PA-X, is expressed from the PA gene segment. PA-X expression is conserved amongst many IAV strains but activity varies between viruses specific for different hosts, suggesting that PA-X also plays a role in host adaptation. Here, we review the role of PA in the emergence of currently circulating H1N1pdm09 viruses and the most recent studies of host adaptive mutations in the PA gene that modulate polymerase activity and PA-X function.

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“…Current influenza vaccines target predominately the variable region of the hemagglutinin protein. This can allow for viruses to escape the immune system via mutation, leading to vaccine mismatch and increased viral spread [19][20][21][22][23][24][25][26][27]. Scientists are continuing work to develop a universal influenza vaccine that targets a less variable region of the influenza virus and is thus protective against a greater breadth of viral strains but, while substantial progress has been made, challenges remain [28][29][30].…”

Section: Introductionmentioning

confidence: 99%

“…Given the relatively error-prone nature of the influenza virus RNA polymerases, mutations are often introduced which can result in viral escape from host immunity through the process of antigenic drift. Such mutations often are selected for in HA as they can lead to an escape from viral neutralization [19][20][21][22][23]. However, antigenic drift can also be seen in other viral proteins [24,25,27,38].…”

Section: Introductionmentioning

confidence: 99%

The Importance of Vaccinating Children and Pregnant Women against Influenza Virus Infection

Misra

Nayak

2019

Pathogens

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Influenza virus infection is responsible for significant morbidity and mortality in the pediatric and pregnant women populations, with deaths frequently caused by severe influenza-associated lower respiratory tract infection and acute respiratory distress syndrome (ARDS). An appropriate immune response requires controlling the viral infection through activation of antiviral defenses, which involves cells of the lung and immune system. High levels of viral infection or high levels of inflammation in the lower airways can contribute to ARDS. Pregnant women and young children, especially those born prematurely, may develop serious complications if infected with influenza virus. Vaccination against influenza will lead to lower infection rates and fewer complications, even if the vaccine is poorly matched to circulating viral strains, with maternal vaccination offering infants protection via antibody transmission through the placenta and breast milk. Despite the health benefits of the influenza vaccine, vaccination rates around the world remain well below targets. Trust in the use of vaccines among the public must be restored in order to increase vaccination rates and decrease the public health burden of influenza.

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Multiple polymerase gene mutations for human adaptation occurring in Asian H5N1 influenza virus clinical isolates

Cited by 20 publications

References 52 publications

Rule-based meta-analysis reveals the major role of PB2 in influencing influenza A virus virulence in mice

Rule-based meta-analysis reveals the major role of PB2 in influencing influenza A virus virulence in mice

Key Role of the Influenza A Virus PA Gene Segment in the Emergence of Pandemic Viruses

The Importance of Vaccinating Children and Pregnant Women against Influenza Virus Infection

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