Mammalian Pathogenesis and Transmission of H7N9 Influenza Viruses from Three Waves, 2013-2015

Belser, Jessica A.; Creager, Hannah M.; Sun, Xiangjie; Gustin, Kortney M.; Jones, Tara L.; Shieh, Wun‐Ju; Maines, Taronna R.; Tumpey, Terrence M.

doi:10.1128/jvi.00134-16

Cited by 21 publications

(23 citation statements)

References 59 publications

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“…Using selected human and AIV controls, we established that our assay yielded results consistent with previously reported pH of fusion (Figure 2). 19, 37, 38, 39 All avian H5 and H7 viruses had relatively high pH of fusion (between pH 5.7 and 6.0), while the pandemic isolates A/California/7/2009(H1N1) and A/Aichi/2/68(H3N2) exhibited lower pH of fusion between pH 5.2 and 5.5, typical of human adapted influenza viruses. 19 The H9N2 viruses examined in this study had pH of fusion that ranged between 5.41 and 5.84.…”

Section: Resultsmentioning

confidence: 99%

Variability in H9N2 haemagglutinin receptor-binding preference and the pH of fusion

Peacock

Benton

Sadeyen

et al. 2017

Emerging Microbes & Infections

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H9N2 avian influenza viruses are primarily a disease of poultry; however, they occasionally infect humans and are considered a potential pandemic threat. Little work has been performed to assess the intrinsic biochemical properties related to zoonotic potential of H9N2 viruses. The objective of this study, therefore, was to investigate H9N2 haemagglutinins (HAs) using two well-known correlates for human adaption: receptor-binding avidity and pH of fusion. Receptor binding was characterized using bio-layer interferometry to measure virus binding to human and avian-like receptor analogues and the pH of fusion was assayed by syncytium formation in virus-infected cells at different pHs. We characterized contemporary H9N2 viruses of the zoonotic G1 lineage, as well as representative viruses of the zoonotic BJ94 lineage. We found that most contemporary H9N2 viruses show a preference for sulphated avian-like receptor analogues. However, the ‘Eastern' G1 H9N2 viruses displayed a consistent preference in binding to a human-like receptor analogue. We demonstrate that the presence of leucine at position 226 of the HA receptor-binding site correlated poorly with the ability to bind a human-like sialic acid receptor. H9N2 HAs also display variability in their pH of fusion, ranging between pH 5.4 and 5.85 which is similar to that of the first wave of human H1N1pdm09 viruses but lower than the pH of fusion seen in zoonotic H5N1 and H7N9 viruses. Our results suggest possible molecular mechanisms that may underlie the relatively high prevalence of human zoonotic infection by particular H9N2 virus lineages.

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Section: Resultsmentioning

confidence: 99%

Variability in H9N2 haemagglutinin receptor-binding preference and the pH of fusion

Peacock

Benton

Sadeyen

et al. 2017

Emerging Microbes & Infections

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“…32 Although HPAI viruses are more often associated with enhanced virulence in ferrets compared with LPAI viruses, intravenous pathogenicity index tests in chickens are not predictive of mammalian virulence. Similarly, virulence determinations in other small mammal models may not always be predictive of virulence in ferrets; viruses that cause moderate disease in ferrets may cause lethality in mice at comparable inoculum doses, 33 whereas the guinea pig model does not recapitulate the high virulence phenotype of H5N1 viruses or the reconstructed 1918 H1N1 virus. 34…”

Section: Scope Of Influenza Viruses Evaluated In Ferretsmentioning

confidence: 99%

A Guide for the Use of the Ferret Model for Influenza Virus Infection

Belser

Eckert

Huynh

et al. 2020

The American Journal of Pathology

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“…To evaluate H7N9 virus replication in epithelial cells, the primary site for replication in mammals, we inoculated cells of the immortalized human airway epithelial cell line Calu-3 with a low dose for evaluation of multicycle replication kinetics. Compared to precursor avian H7 and H9 viruses, LPAI H7N9 viruses have demonstrated an enhanced ability to replicate in human airway epithelial Calu-3 cells, suggestive of mammalian host adaptation (26). The recent amino acid changes associated with select fifth-wave H7N9 viruses prompted us to compare their growth kinetics in this cell type.…”

Section: Resultsmentioning

confidence: 99%

“…Ferrets have been extensively employed to evaluate the pandemic potential of newly emerged influenza A viruses (28). The LPAI H7N9 viruses from previous waves were able to cause moderate weight loss and replicate efficiently in both the upper and lower respiratory tracts of ferrets (12,26). To evaluate the virulence of fifth-wave H7N9 viruses, we i.n.…”

Section: Resultsmentioning

confidence: 99%

Risk Assessment of Fifth-Wave H7N9 Influenza A Viruses in Mammalian Models

Sun

Belser

Pappas

et al. 2019

J Virol

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The fifth wave of the H7N9 influenza epidemic in China was distinguished by a sudden increase in human infections, an extended geographic distribution, and the emergence of highly pathogenic avian influenza (HPAI) viruses. Genetically, some H7N9 viruses from the fifth wave have acquired novel amino acid changes at positions involved in mammalian adaptation, antigenicity, and hemagglutinin cleavability. Here, several human low-pathogenic avian influenza (LPAI) and HPAI H7N9 virus isolates from the fifth epidemic wave were assessed for their pathogenicity and transmissibility in mammalian models, as well as their ability to replicate in human airway epithelial cells. We found that an LPAI virus exhibited a similar capacity to replicate and cause disease in two animal species as viruses from previous waves. In contrast, HPAI H7N9 viruses possessed enhanced virulence, causing greater lethargy and mortality, with an extended tropism for brain tissues in both ferret and mouse models. These HPAI viruses also showed signs of adaptation to mammalian hosts by acquiring the ability to fuse at a lower pH threshold than other H7N9 viruses. All of the fifth-wave H7N9 viruses were able to transmit among cohoused ferrets but exhibited a limited capacity to transmit by respiratory droplets, and deep sequencing analysis revealed that the H7N9 viruses sampled after transmission showed a reduced amount of minor variants. Taken together, we conclude that the fifth-wave HPAI H7N9 viruses have gained the ability to cause enhanced disease in mammalian models and with further adaptation may acquire the ability to cause an H7N9 pandemic. IMPORTANCE The potential pandemic risk posed by avian influenza H7N9 viruses was heightened during the fifth epidemic wave in China due to the sudden increase in the number of human infections and the emergence of antigenically distinct LPAI and HPAI H7N9 viruses. In this study, a group of fifth-wave HPAI and LPAI viruses was evaluated for its ability to infect, cause disease, and transmit in small-animal models. The ability of HPAI H7N9 viruses to cause more severe disease and to replicate in brain tissues in animal models as well as their ability to fuse at a lower pH threshold than LPAI H7N9 viruses suggests that the fifth-wave H7N9 viruses have evolved to acquire novel traits with the potential to pose a higher risk to humans. Although the fifth-wave H7N9 viruses have not yet gained the ability to transmit efficiently by air, continuous surveillance and risk assessment remain essential parts of our pandemic preparedness efforts.

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Mammalian Pathogenesis and Transmission of H7N9 Influenza Viruses from Three Waves, 2013-2015

Cited by 21 publications

References 59 publications

Variability in H9N2 haemagglutinin receptor-binding preference and the pH of fusion

Variability in H9N2 haemagglutinin receptor-binding preference and the pH of fusion

A Guide for the Use of the Ferret Model for Influenza Virus Infection

Risk Assessment of Fifth-Wave H7N9 Influenza A Viruses in Mammalian Models

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