Rapid emergence of a virulent PB2 E627K variant during adaptation of highly pathogenic avian influenza H7N7 virus to mice

Jong, Rineke M C de; Stockhofe-Zurwieden, Norbert; Verheij, Eline; Boer-Luijtze, Els A. de; Ruiter, Saskia J M; Leeuw, Olav S. de; Cornelissen, Lisette A. H. M.

doi:10.1186/1743-422x-10-276

Cited by 29 publications

(23 citation statements)

References 39 publications

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“…Selected H7 viruses, like the H7N9 LPAI virus, with such mammalian adaption markers have emerged and exhibited increased virulence in animal models (14). Moreover, the PB2 627K mutation present in the H7N7 HPAI NL/219 virus was also found to be responsible for its lethal phenotypes in mammals (32). Sequence analysis of two recently emerged H7N8 viruses reveals no such substitutions, indicating that H7N8 viruses have not become well adapted to infect mammals.…”

Section: Discussionmentioning

confidence: 99%

Pathogenesis and Transmission Assessments of Two H7N8 Influenza A Viruses Recently Isolated from Turkey Farms in Indiana Using Mouse and Ferret Models

Sun

Belser

Pulit-Penaloza

et al. 2016

J Virol

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Avian influenza A H7 viruses have caused multiple outbreaks in domestic poultry throughout North America, resulting in occasional infections of humans in close contact with affected birds. In early 2016, the presence of H7N8 highly pathogenic avian influenza (HPAI) viruses and closely related H7N8 low-pathogenic avian influenza (LPAI) viruses was confirmed in commercial turkey farms in Indiana. These H7N8 viruses represent the first isolation of this subtype in domestic poultry in North America, and their virulence in mammalian hosts and the potential risk for human infection are largely unknown. In this study, we assessed the ability of H7N8 HPAI and LPAI viruses to replicate in vitro in human airway cells and in vivo in mouse and ferret models. Both H7N8 viruses replicated efficiently in vitro and in vivo, but they exhibited substantial differences in disease severity in mammals. In mice, while the H7N8 LPAI virus largely remained avirulent, the H7N8 HPAI virus exhibited greater infectivity, virulence, and lethality. Both H7N8 viruses replicated similarly in ferrets, but only the H7N8 HPAI virus caused moderate weight loss, lethargy, and mortality. The H7N8 LPAI virus displayed limited transmissibility in ferrets placed in direct contact with an inoculated animal, while no transmission of H7N8 HPAI virus was detected. Our results indicate that the H7N8 avian influenza viruses from Indiana are able to replicate in mammals and cause severe disease but with limited transmission. The recent appearance of H7N8 viruses in domestic poultry highlights the need for continued influenza surveillance in wild birds and close monitoring of the potential risk to human health. IMPORTANCE H7 influenza viruses circulate in wild birds in the UnitedStates, but when the virus emerges in domestic poultry populations, the frequency of human exposure and the potential for human infections increases. An H7N8 highly pathogenic avian influenza (HPAI) virus and an H7N8 low-pathogenic avian influenza (LPAI) virus were recently isolated from commercial turkey farms in Indiana. To determine the risk that these influenza viruses pose to humans, we assessed their pathogenesis and transmission in vitro and in mammalian models. We found that the H7N8 HPAI virus exhibited enhanced virulence, and although transmission was only observed with the H7N8 LPAI virus, the ability of this H7 virus to transmit in a mammalian host and quickly evolve to a more virulent strain is cause for concern. Our findings offer important insight into the potential for emerging H7 avian influenza viruses to acquire the ability to cause disease and transmit among mammals.

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Section: Discussionmentioning

confidence: 99%

Pathogenesis and Transmission Assessments of Two H7N8 Influenza A Viruses Recently Isolated from Turkey Farms in Indiana Using Mouse and Ferret Models

Sun

Belser

Pulit-Penaloza

et al. 2016

J Virol

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“…Such evolution has been observed in a fatal human case of influenza A/H7N7 (Jonges et al, 2014) and in mouse experiments following serial lung passage using an isolate from this outbreak (de Jong et al, 2013). Lys at position 627 has also been associated with greater severity in zoonotic H7N9 (Sha et al, 2016) and H5N1 (de Jong et al, 2006) cases However, reverse genetics experiments show that certain strains of avian influenza may be less able to accept these mutations than others (Long et al, 2013).…”

Section: Trait 3: Polymerase Complex Efficiencymentioning

confidence: 80%

Viral factors in influenza pandemic risk assessment

Lipsitch

Barclay

Raman

et al. 2016

eLife

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The threat of an influenza A virus pandemic stems from continual virus spillovers from reservoir species, a tiny fraction of which spark sustained transmission in humans. To date, no pandemic emergence of a new influenza strain has been preceded by detection of a closely related precursor in an animal or human. Nonetheless, influenza surveillance efforts are expanding, prompting a need for tools to assess the pandemic risk posed by a detected virus. The goal would be to use genetic sequence and/or biological assays of viral traits to identify those non-human influenza viruses with the greatest risk of evolving into pandemic threats, and/or to understand drivers of such evolution, to prioritize pandemic prevention or response measures. We describe such efforts, identify progress and ongoing challenges, and discuss three specific traits of influenza viruses (hemagglutinin receptor binding specificity, hemagglutinin pH of activation, and polymerase complex efficiency) that contribute to pandemic risk.DOI: http://dx.doi.org/10.7554/eLife.18491.001

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“…Similarly, the presence of a lysine at this position in LPAI H7N9 human isolates and a mouse-adapted H7N7 equine virus resulted in increased PB2 polymerase activity, viral loads, and disease severity in mice (Mok et al 2014; Shinya et al 2007; Zhang et al 2013, 2014). Enhanced virulence of HPAI H7N7 viruses bearing E627K was also observed in ferrets compared with virus bearing glutamic acid at this position (de Jong et al 2013). However, H7N9 viruses bearing either a glutamic acid or lysine at position 627 exhibited comparable transmissibility in the ferret model, indicating E627K does not solely confer an enhanced transmissibility phenotype (Zhang et al 2013).…”

Section: Molecular and Host Determinants Of Pathogenicity And Transmentioning

confidence: 99%

“…As mentioned in preceding sections, several studies have demonstrated a similar role for this position among H7 subtype viruses. An E627K substitution in a HPAI H7N7 virus isolated from the Netherlands was identified as a major determinant of mammalian pathogenicity, with viruses bearing this mutation exhibiting increased viral load, extrapulmonary spread to the brain, and heightened mortality in mice; this enhanced virulence was absent in mice inoculated with virus bearing the reciprocal K627E mutation (de Jong et al 2013; Munster et al 2007). Similarly, the presence of a lysine at this position in LPAI H7N9 human isolates and a mouse-adapted H7N7 equine virus resulted in increased PB2 polymerase activity, viral loads, and disease severity in mice (Mok et al 2014; Shinya et al 2007; Zhang et al 2013, 2014).…”

Section: Molecular and Host Determinants Of Pathogenicity And Transmentioning

confidence: 99%

Mammalian Models for the Study of H7 Virus Pathogenesis and Transmission

Belser

Tumpey

2014

Influenza Pathogenesis and Control - Volume I

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Mammalian models, most notably the mouse and ferret, have been instrumental in the assessment of avian influenza virus pathogenicity and transmissibility, and have been used widely to characterize the molecular determinants that confer H5N1 virulence in mammals. However, while H7 influenza viruses have typically been associated with conjunctivitis and/or mild respiratory disease in humans, severe disease and death is also possible, as underscored by the recent emergence of H7N9 viruses in China. Despite the public health need to understand the pandemic potential of this virus subtype, H7 virus pathogenesis and transmission has not been as extensively studied. In this review, we discuss the heterogeneity of H7 subtype viruses isolated from humans, and the characterization of mammalian models to study the virulence of H7 subtype viruses associated with human infection, including viruses of both high and low pathogenicity and following multiple inoculation routes. The use of the ferret transmission model to assess the influence of receptor binding preference among contemporary H7 influenza viruses is described. These models have enabled the study of preventative and therapeutic agents, including vaccines and antivirals, to reduce disease burden, and have permitted a greater appreciation that not all highly pathogenic influenza viruses are created equal.

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Rapid emergence of a virulent PB2 E627K variant during adaptation of highly pathogenic avian influenza H7N7 virus to mice

Cited by 29 publications

References 39 publications

Pathogenesis and Transmission Assessments of Two H7N8 Influenza A Viruses Recently Isolated from Turkey Farms in Indiana Using Mouse and Ferret Models

Pathogenesis and Transmission Assessments of Two H7N8 Influenza A Viruses Recently Isolated from Turkey Farms in Indiana Using Mouse and Ferret Models

Viral factors in influenza pandemic risk assessment

Mammalian Models for the Study of H7 Virus Pathogenesis and Transmission

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